Results

Study Flow

We identified and retrieved 5,185 references (Figure 2). We excluded 3,452 references (Appendix B). We included 905 references for this review. Abstracted data is available at https://netfiles.umn.edu/xythoswfs/webui/_xy-17667196_1-t_lUjda8AM. Eligible references presented the results from individual studies, several publications of the same study, pooled analyses of the aggregate data, pooled analyses of the individual patient data, or statistical analyses of several studies with strength of evidence (Appendix Table F1). As an example of the latter, the FDA medical and statistical reviews contained 43 eligible studies (Appendix Table F2).

Key Question 1. What constitutes an adequate diagnostic evaluation in the ambulatory care setting on which to base treatment of urinary incontinence (UI)?

Reporting quality of the studies precluded definitive conclusions about methodological quality (Appendix Table F3).151,166 We did not identify the studies that reported sensitivity or specificity of different methods when compared to bladder diaries.

We summarized diagnostic values of diagnostic methods to differentiate stress, urgency, and mixed UI when compared to multichannel urodynamics or to clinical diagnosis. Described use of urodynamic testing as a reference standard test was very similar across the studies. Diagnostic methods to establish a clinical diagnosis of UI were described with different levels of detail and included history, physical examination, pelvic examination, urine culture, Q-tip test, diary, cytometry,218 cough stress test, 48-hour home pad test,259 evaluation of sacral nerves 2 to 4 (deep tendon reflexes, anal wink, perineal sensation), and measurement of postvoid residual volume (by catheter or ultrasonography).

Diagnostic Evaluation for UI

Diagnostic Value of the Symptoms of Stress UI To Distinguish Urodynamic Stress UI Was Low

The diagnostic value of the symptoms of urgency UI compared to multichannel urodynamics to distinguish detrusor overactivity was examined in 23 studies of 5,485 patients (Appendix Table F7).188,191,195,200,202,203,213,216,217,228,229,238,244,246,251,273,279–281,284 Sensitivity varied across the individual studies from 14 percent280 to more than 90 percent.188,216,244,251,279,284 Specificity varied across the individual studies from 21 percent207 to more than 90 percent.203,280 Pooled sensitivity was 82 percent (95 percent CI, 76 to 87 percent) (Appendix Figure F4) for any detrusor overactivity while pooled specificity was as low as 51 percent (95 percent CI, 44 to 59 percent) (Appendix Figure F5). The positive predictive likelihood ratio was small at 1.5 (95 percent CI, 1.4 to 1.7).

Diagnostic Value of Complex Clinical Algorithms

The diagnostic values of complex clinical algorithms were high and varied depending on components of algorithms and reference methods to diagnose UI.

Diagnostic Value of a Clinical Algorithm Versus Urodynamics

Diagnostic value of complex clinical algorithms for UI was high when compared to urodynamic evaluation. Two studies examined diagnostic value of algorithms for stress UI. One study of 1,455 women examined diagnostic value of a clinical algorithm versus urodynamics. Included subjects had predominant symptoms of stress UI with more than four episodes of UI per week, normal diurnal and nocturnal frequency, a bladder capacity of 400 ml or greater, and a positive cough stress (sign of stress UI) and stress pad test.254 The authors reported positive predictive values of 90.2 percent for urodynamic stress UI and 76.9 percent for pure urodynamic stress UI.254 Diagnostic accuracy was the same across age categories and among those with previous surgery for stress UI.254 The authors did not report positive predictive likelihood of the clinical algorithm. Another study of 652 women examined the diagnostic value of a clinical algorithm that required the presence of a predominant complaint of stress UI, positive cough stress test results, postvoid residual urine volume of no more than 50 ml, and a functional bladder capacity of at least 400 ml as determined by a completed 24-hour frequency volume chart.230 This study also used urodynamics as a reference standard test. The algorithm had a positive predictive value of 97 percent when compared to multichannel urodynamics to diagnose stress UI.230

One study examined diagnostic value of algorithms for urgency UI. The diagnosis of pure detrusor overactivity was accurate when compared to urodynamics in scoring frequency, urgency, nocturia, and self-reported urgency UI.276,277 The algorithm demonstrated good diagnostic value with a positive predictive likelihood ratio of 12.6 and a diagnostic odds ratio of 27.3. The same study proposed scoring of urodynamic stress UI based on self-reported frequency of incontinent episodes and the amount of protection.276,277 The diagnostic value of such composite scores was moderate with a positive predictive likelihood ratio of 3.8 and a diagnostic odds ratio of 11.

Diagnostic Value of Clinical Algorithms Based on the Epidemiology of a Pelvic Organ Prolapse and Incontinence Questionnaire When Compared to Clinical Diagnosis

This comparison was tested in one study of 110 women.262 The questionnaire had a moderate likelihood of identifying women with detrusor overactivity (positive likelihood ratio=7.7) and a large likelihood of identifying women with stress UI (positive likelihood ratio=19).262 One study demonstrated moderate diagnostic value of the Three Incontinence Questions Questionnaire (3IQ) when compared to clinical diagnosis in 301 women to detect those with stress or urgency UI.266

Diagnostic Values of Individual Tests When Compared to Urodynamics

In individual studies, other examined tests using urodynamics as a reference standard, including the Q-tip test,208,286 UDI-6,244,287 questionnaire for urinary incontinence diagnosis (QUID) stress score,288 or Bristol Female Lower Urinary Tract Symptoms Questionnaire,253 demonstrated minimal diagnostic value for UI with positive predictive likelihood ratios less than 2 (Table 3). The studies of the Gaudenz questionnaire reported different results depending on the country where the study was conducted.220,238

Diagnostic Values of Ultrasound Versus Urodynamics as a Reference Standard

The diagnostic values of ultrasound using urodynamics as a reference standard were examined in five studies of 540 women.289–293 Perineal ultrasound had a small diagnostic value with a positive predictive likelihood ratio of 3 for urodynamic stress UI.289 Vaginal ultrasound had a moderate diagnostic value with a positive predictive likelihood ratio of 5.3 for urodynamic stress UI.293 Transrectal ultrasound that detected a decreased angle of UV junction demonstrated a large and conclusive increase in the likelihood of urodynamic stress UI.291,292

Comparison of Diagnostic Values of Different Tests

The majority of studies demonstrated that the tests had only small diagnostic value in distinguishing women with urodynamic stress or urgency UI. Complex clinical algorithms demonstrated better diagnostic performance. Individual studies suggested a good diagnostic value of the epidemiology of prolapse and incontinence questionnaires. Post-test probability of mixed or urgency UI increased in aging women.294

We compared the accuracy of diagnostic tests for different types of UI across studies (Table 3). Urodynamic stress UI was accurately diagnosed in 80 percent of women using 1-hour pad test, and in 75 percent of women using self-reported symptoms of stress UI (Figure 3). Urge symptoms accurately diagnosed urodynamic urgency UI in 66 percent of women. Pad tests accurately diagnosed urodynamic urgency UI in 61 percent of women. Accuracy of the symptoms of mixed UI to diagnose urodynamic stress UI combined with detrusor overactivity was low (56 percent). Clinical diagnosis of stress UI was accurately detected with self-reported symptoms of stress UI in 80 percent of women. Clinical diagnosis of detrusor overactivity was accurately detected with self-reported symptoms of urgency UI in 73 percent. The pooled diagnostic odds ratio demonstrated the same pattern with the best discriminatory performance of symptoms of stress UI and pad test when compared to urodynamic diagnosis of stress UI (Figure 4). The diagnostic odds ratio was the more than 10 for the symptoms for stress and urgency UI when compared to a clinical diagnosis.

We also compared predictive values of diagnostic tests for different type of UI across the studies (Table 4). The predictive values in ambulatory settings depend on prevalence of UI in community dwelling women.167 Positive predictive values were less than 50 percent for most comparisons while negative predictive values were larger than 90 percent. Positive predictive value of the symptoms of mixed UI and urgency UI increased with age. The majority of women without symptoms of UI did not have clinical diagnosis of UI.

Predictive value of diagnostic tests for different types of UI by age subgroups.

Minimal Clinically Important Differences in Diagnostic Tools To Monitor Effectiveness of Treatments

Women considered a reduction of 50 percent or more in UI episode frequency a clinical success.295 Quality of life was improved with more than 70 percent reduction in UI episode frequency. However, clinical trials and the FDA reviews did not define women centered outcomes as primary outcomes.

Clinically important differences have been determined for several questionnaires and scales. Among validated diagnostic questionnaires, The Leicester Urinary Symptom Questionnaire (LUSQ)296 and Medical, Epidemiological, and Social Aspects of Aging Questionnaire (MESA)297 provided information about presence and severity of UI in categorical terms. Other tools suggested scoring of the symptoms of any UI259,298 or urgency UI.264 The overall score varied for different tools (Table 5). The Bladder Self-Assessment Questionnaire and Bladder Control Self-Assessment Questionnaires defined minimal important differences in scores that can be used to detect treatment success in clinical settings.299

Diagnostic tools to assess clinical importance and monitor effectiveness of treatments of UI.

A variety of validated tools are available to monitor quality of life in women with UI and with different UI types. Several tools that define clinically important differences in scores can be used to assess treatment success in clinical settings.

Patient satisfaction can be assessed with several validated tools, including the Overactive Bladder Symptom Score,300 the Benefit, Satisfaction with Treatment, and Willingness,301 the Estimated Percent Improvement,328 or the Global Perception of Improvement302 (Table 5). Some tools focused on satisfaction with treatments in women with urgency UI,300,301,303 while other tools were proposed for any UI type. These instruments are brief and do not require much time to complete. Clinical importance of different responses is self-explanatory. Patient satisfaction measures define treatment success but do not provide many details to explain treatment failure.

We analyzed validity and reliability of the tools and sought literature to find definitions of the minimum important differences in continuous measures of severity of UI, bothersomeness, or quality of life (Table 5). We evaluated the scales and questionnaires recommended by the ICI for diagnosis, monitoring of treatment, and assessment of quality of life in women with UI.304

Effectiveness of treatments in randomized controlled clinical trials was assessed with 3 to 7 day diaries. A reduction in UI episode frequency was the most common primary outcome that RCTs were designed to examine.115,305–326 Medical and statistical reviews conducted by the FDA focused on the same primary outcomes that RCTs were designed to examine—absolute changes in UI episode frequency.115,306,307,327–330 Some RCTs further categorized treatment success as any reduction in UI episode frequency or reduction by 50, 75, or 90 percent in UI episode frequency.

One pooled analysis of individual data of 1,913 women with predominant stress UI who participated in four RCTs examined what reduction in UI episode frequency was important for the patients.295 The authors examined the relationship between relative reduction in UI episode frequency and improvement meaningful for women in the Incontinence Quality of Life questionnaire.295 Women with daily stress UI perceived important clinical benefit at reductions of approximately 50 percent and important incremental clinical value at reductions of 75 percent and 90 to 100 percent. The study concluded that women noticed improvement in quality of life when UI episode frequency was reduced by more than 70 percent.295 Small changes of 20 to 40 percent in incontinence episode frequency were not important to women when the results from a voiding diary were analyzed in association with the validated Incontinence Quality of Life (I-QOL) questionnaire. The quality of life impact was similar for stress UI episode reductions of >40 percent to <70 percent.295 In the case of women with persistent urge, stress or mixed urinary incontinence, more than 60 percent reported complete treatment satisfaction using the Global Perception of Improvement of Incontinence Impact Questionnaire when they experienced a more than 70 percent reduction in UI episode.302 No studies examined clinically important reduction in UI episode frequency for women with predominant urgency UI.

All tools to assess symptom bother have been validated. Tools that distinguish symptom bother for stress UI include Patient Global Impression of Improvement PGI-I,331 PGI-S Patient Global Impression of Improvement and Severity,331 or Symptom Severity Index and Symptom Impact Index for stress UI in women.332 The Primary OAB Symptom Questionnaire provided four scales to assess symptom bother for urgency UI.333 Other tools evaluated symptom bother for any type of UI (Table 5). The Incontinence Severity Index,334,335 Patient Global Impression of Improvement and of Severity,331 Urogenital Distress Inventory,222,336,337 and Patient Perception of Bladder Condition333,338,339 developed definitions of minimum important differences in any UI that can be used to define treatment success in clinical settings. The Urogenital Distress Inventory stress subscale also can distinguish minimum important differences in stress UI.336 Women reported improvement in UI when the incontinence episode frequency was reduced by ≥63percent.331

Several tools have been validated to assess quality of life in women with UI (Table 5). All tools provided scoring for different domains of quality of life and overall total scores that varied by direction and magnitude across the scales. Comparing efficacy of the tools was difficult because of such variability in content and psychometric properties. Few tools addressed quality of life depending on the type of incontinence.

Association Between Methods of Diagnosis and Prediction of Patient Outcomes

We found no evidence that outcomes of conservative treatments were better predicted by urodynamic diagnosis.

However, women who failed conservative treatments and/or decided to have surgery for stress UI may benefit from a multichannel urodynamic evaluation. In all cases, a diagnostic algorithm assumes adequate assessment of baseline conditions that may result in UI, including pelvic organ prolapse, urinary tract infection, or pelvic floor trauma.

A few studies tested the effect of baseline urodynamic examination in association with better prediction of treatment outcomes. The studies generally showed that urodynamic findings did not better predict response to conservative treatments. One extension of RCTs of conservative treatment concluded that continence (RR 1.24, 95 percent CI, 0.30 to 5.23), improvement in UI (RR 0.85, 95 percent CI, 0.55 to 1.31), or treatment failure with worsening of UI (RR 1.24, 95 percent CI, 0.47 to 3.29) did not differ between women who did or did not have a baseline urodynamic evaluation.340 The second RCT randomized women to conservative treatments depending on baseline urodynamics or clinical symptoms.341 Treatments included fluid management, physical therapy, and drugs, depending on urodynamic or clinical diagnosis. Quality of life measured with King’s Health Questionnaire and the frequency of UI episodes measured with voiding diary did not differ between randomized groups.341 The authors concluded that baseline urodynamic diagnosis was not associated with better predicting outcomes.

Drug studies showed that in women with severe stress UI, duloxetine versus placebo decreased the frequency of UI episodes independent of baseline urodynamic findings.319 Women with intrinsic sphincter deficiency experienced more than a 50 percent decrease in daily UI (RR 6.15, 95 percent CI, 1.54 to 24.54), as did women without intrinsic sphincter deficiency (RR 4.20, 95 percent CI, 1.81 to 9.76). The RCT, however, was not designed to detect differences in duloxetine effect by using a baseline urodynamic evaluation. One multicenter RCT examined clinical outcomes with fesoterodine in subgroups by urodynamic findings of detrusor overactivity.342 Treatment response, discontinuation rate, and adverse effects did not differ between individuals with versus without urodynamic diagnosis of detrusor overactivity (Appendix Table F25).342 One RCT that compared clinical outcomes with tolterodine-ER versus placebo also did not demonstrate differences in treatment effects in women with and without urodynamic detrusor overactivity.343 Baseline urodynamic examination did not better predict treatment outcomes. Case series also found no differences in treatment response with oxybutynin between those with versus without urodynamically verified symptoms (Appendix Table F26).344

In contrast, one large analysis of 6,276 women with UI from the United Kingdom suggested that urodynamic evaluation is essential to predict outcomes, but only with surgery for UI.345 The authors examined the accuracy of the history of pure stress UI in predicting only urodynamic stress UI compared to the NICE guidance and found very low sensitivity of 11 percent and good specificity of 98 percent (NICE, 83 percent; 95 percent CI, 49 to 92 percent). The study suggested that a multichannel urodynamic evaluation is indicated for women whose conservative treatments failed and who decided to have surgery for stress UI.345 A recent study also concluded that all women whose conservative treatments failed and who undergo surgery for stress UI should have multichannel urodynamic evaluation.346

Key Question 2. How effective is the pharmacological treatment of UI in women?

We synthesized evidence of efficacy and comparative effectiveness of the drugs for stress UI, including topical estrogen and serotonin-noradrenalin uptake inhibitors and drugs used in the treatment of overactive bladder.69 We integrated information about inclusion, exclusion criteria, sponsorship, conflict of interest (Appendix Table F27) and quality of the studies (Appendix Table F28) in the synthesis of evidence. We report here study characteristics that could influence the treatment effects of drugs for UI.

Pharmacological Treatments for Stress UI

Clinical Effectiveness of Topical Estrogen Therapy

Evidence from individual RCTs indicated greater continence and improvement in UI with vaginal estrogen formulations and worsening of UI with transdermal patches (Appendix Table F29). Evidence was insufficient to draw conclusions about clinical efficacy of different topical estrogen treatments for UI.

Four RCTs of 640 women examined the effects of topical estrogen formulations compared to placebo on UI (Appendix Table F27). The studies enrolled postmenopausal women with urodynamic stress,379,380 clinical symptoms of any UI,381 clinical symptoms of any UI,381 or with urge syndrome.382 Estrogen was administered in vaginal tablets, gel,379 subcutaneous implants,382 intravaginal ovules,380 or transdermal patches.380,381 The length of treatment varied from 6 months379 to 2 years.381 Three studies aimed to treat UI.379,380,382 One study examined very low dose transdermal estrogen formulation proposed for prevention of osteoporosis in postmenopausal women.381

Improvement in UI

Improvement in UI was significantly greater than placebo with vaginal estrogen tablets379 and vaginal ovules380 (Appendix Table F31). Women complained of stress UI less frequently with intravaginal estrogen formulations than with placebo.380 Unchanged incontinence was less frequent with intravaginal estrogen than with placebo.379 In contrast, transdermal patches with very low doses of estrogen worsened any UI and stress UI at 2 years381 (Appendix Table F32). Adjusted for clinical site odds ratios of worsened UI demonstrated increases in odds of stress UI at 4 months (OR 2.05, 95 percent CI, 1.09 to 3.85) but not 4 years. In addition to worsening of UI, women experienced vaginal bleeding with estradiol implants more often than with placebo.382

Clinical Effectiveness of Duloxetine

A high level of evidence indicated significant improvement in stress UI with duloxetine, while a low level of evidence suggested that duloxetine did not resolve stress UI when compared to placebo. A low level of evidence suggested improvement in quality of life in women with UI. Evidence was insufficient to conclude benefits of duloxetine in women with urgency UI. The risk of adverse effects was significantly higher with duloxetine than with placebo. Duloxetine resulted in improved UI in 75 to 140 women per 1,000 treated,319,364,383–387 while 129 women per 1,000 treated stopped taking duloxetine because of adverse effects.

Improvement in UI

Women experienced more than a 50 percent reduction in the frequency of UI episodes with duloxetine319,364,384,386,387 (Appendix Table F36). More women perceived an improvement in UI as either much better or better with duloxetine than with placebo319,383–385 (Appendix Table F36). Seven women had to take duloxetine to achieve a 50 percent reduction in UI episodes in one woman (Table 6). Thirteen women (NNT 13, 95 percent CI, 7 to 143) needed to be treated so one woman would perceive an improvement as either much better or better. Improvement in UI was greater with 40 mg/day compared to 20 mg/day390 (Appendix Table F37). Treatment failure did not differ between duloxetine and placebo319,383,385,402 (Appendix Table F38).

Improvement in quality of life measures with duloxetine was inconsistent across the studies. Quality of life was examined in eight studies of 5,001 women319,364,384–386,390,391,398 (Appendix Table F39). Pooled analysis of two RCTs of 1,133 women with predominant stress UI demonstrated improved Incontinence Quality of Life scores using 80 mg of duloxetine.364 The Multinational Duloxetine UI Study Group found significant improvement in quality of life in North American women,391 with no benefit for women in other continents.384 One study indicated significant dose response improvements in the Incontinence Quality of Life questionnaire with 40 mg compared to 20 mg of duloxetine/day.390 Women with severe stress UI319 and women with overactive bladder did not experience better quality of life with duloxetine385 compared to placebo.

Adverse Effects

Adverse effects with duloxetine versus placebo were examined in 15 studies with 26,703 subjects.319,383–387,389–393,397,401,402,404 Results demonstrated the importance of definitions and measurements of harms. Studies of any adverse effects or treatment-related adverse effects (as judged by investigators) reported less relative harm from the drug than studies of individual adverse effects. For example, the relative increase in treatment-related adverse effects (as judged by investigators) was 36 percent (pooled RR 1.36, 95 percent CI, 1.28 to 1.44)319,383–387,391,392,401 (Appendix Table F40). At the same time, the relative increase in several harms was much larger. For instance, relative increase in somnolence was 761 percent (pooled RR 8.61, 95 percent CI, 4.58 to 16.20).319,383–387,389,391–393,397,401,402 Nausea (NNT 5, 95 percent CI, 4 to 7),319,384,390,392,393,397,401 dry mouth (NNT 9, 95 percent CI, 7 to 11),319,383–387,389–393,397,401,402 and fatigue (NNT 13, 95 percent CI, 10 to 19)319,383–387,390–392,397,401,402 were among the most common adverse effects of duloxetine when compared to placebo (Appendix Table F41).

The studies did not show consistent dose response associations between duloxetine and adverse effects (Appendix Table F42). The Duloxetine Dose Escalation study reported lower risks of adverse effects at a starting dose of 20 mg with slow escalation to 80 mg/day.389 Large pooled analysis that examined cardiovascular adverse effects of duloxetine403 demonstrated electrocardiographic abnormalities that were statistically but not clinically significant.

Women stopped taking duloxetine because of adverse effects more often than placebo (Appendix Table F43). The relative increase in discontinuation of duloxetine treatment for any adverse effects was 340 percent (pooled RR 4.4, 95 percent CI, 3.24 to 5.86).319,383,384,386,389–392,394,402 Discontinuation rates differed across the studies. We explored heterogeneity by women’s age, prior treatments, and concurrent medications for UI, and baseline type and severity of UI (Appendix Table F44) and did not find significant association with the outcome (Appendix Table F45). We explored heterogeneity by study quality (Appendix Table F46) and did not find significant association with the outcome (Appendix Table F45).

Pharmacological Treatments for Urgency UI

Clinical Effectiveness of Oxybutynin

A high level of evidence indicated that oxybutynin increased continence rates and improved UI more often than placebo but also resulted in treatment discontinuation due to adverse effects (see Table ES2 in the Executive Summary). Dry mouth was the most common adverse effect. Oxybutynin resulted in resolved UI in 114 women per 1,000 treated, while 63 women per 1,000 treated stopped taking oxybutynin because of adverse effects. Evidence was insufficient to conclude improved quality of life with oxybutynin. A low level of evidence indicated greater rates of adverse effects and dry mouth with immediate release oxybutynin than with controlled release oral or transdermal oxybutynin. A low level of evidence indicated that larger versus lower doses of extended oxybutynin resulted in greater improvement in UI and the same rates of dry mouth, but greater treatment withdrawal.

We identified 15 publications of individual RCTs,115,310,322,405–416 one RCT of intravesicular injection of oxybutynin in 52 women,417 one post hoc analysis of RCTs,418 and 10 RCTs that compared different doses and formulations of oxybutynin419–428 (Appendix Table F27). We also reviewed a noncontrolled Ditropan XL study of 256 women,429 a Multicentre Assessment of Transdermal Therapy in Overactive Bladder With Oxybutynin (MATRIX) study of 2,888 women, pooled analysis of dosing studies,323,430,431 and five observational studies of harms and discontinuation rates of oxybutynin therapy432–436 (Appendix Table F33).

Continence

Urinary continence was greater with oxybutynin than with placebo409,413,416,437,438 (Appendix Table F47). Pooled results were consistent with nonsignificant heterogeneity across the studies despite differences in populations and doses of the drug. The pooled results, however, were sensitive to one multicenter study at 76 clinics in the United States that demonstrated significant increase in resolved UI with oxybutynin.413 The drug needed to be given to nine women to achieve continence in one woman (Table 7).

Improvement in UI

Oxybutynin improved UI more often than placebo322,406,415,416,418,437–443 (Appendix Table F47). The drug needed to be given to six women to improve UI in one woman (Table 7). The magnitude of the effect varied across the studies with significant heterogeneity in pooled estimates. Dose of the drug did not explain heterogeneity (p value for meta-regression >0.5). Differences in definitions of improved UI may contribute to heterogeneity. The studies that defined improvement as a reduction of 75 percent in UI episodes415,437 reported similar relative risk and absolute risk difference. In contrast, the studies that did not quantify improvement in UI tended to demonstrate very large benefits from oxybutynin compared to placebo (Appendix Table F47).

We explored heterogeneity by characteristics of women, treatment, and study and found no significant association with the outcomes (Appendix Table F48).

Change in quality of life was inconsistent within and across the studies407,410,437,442,444 (Appendix Tables F49 and F50). Transdermal oxybutynin did not improve quality of life and did not result in treatment satisfaction compared to placebo in women with overactive bladder (OAB).445

Adverse Effects

Discontinuation of treatments did not differ between oxybutynin and placebo406,413,437,439,446 (Appendix Table F47). However, discontinuation of treatment due to adverse effects was greater with active drugs than with placebo (Appendix Table F47).87,412,413,441,442,446 Among every 16 treated, one woman stopped taking the drug because of adverse effects. Interestingly, the relative increase in total adverse effects411,439,441 or serious adverse effects411,413,441 did not differ from placebo (Appendix Table F47). The differences across the studies in definitions and methods to assess harms may contribute to discrepancies.

The Transdermal Oxybutynin Study found that severe dry mouth and constipation were less common with transdermal than with oral immediate-release oxybutynin.423 Adverse effects were less common with once-daily, controlled-release formulation oxybutynin than with immediate-release oxybutynin.447 Dry mouth was less common with transdermal versus oral immediate-release oxybutynin,423 with controlled versus immediate-release oxybutynin,419 and with lower versus larger doses of controlled-release oxybutynin.427

Clinical Effectiveness of Tolterodine

A high level of evidence indicated increased continence rates and significant improvement in UI with tolterodine treatments than with placebo in women with UI (see Table ES2 in the Executive Summary). A low level of evidence indicated improvement in quality of life with tolterodine treatment. Adverse effects including autonomic nervous system disorders, abdominal pain, dry mouth, dyspepsia, and fatigue were significantly more common with tolterodine than with placebo. Per 1,000 women treated, tolterodine resulted in resolved UI in 85 women, and resulted in adverse effects in 83 women. Discontinuation of the treatment and stopping treatment due to adverse effects did not differ between tolterodine and placebo.

Continence

Urinary continence was achieved more often with tolterodine than with placebo in pooled analysis (pooled RR 1.2, 95 percent CI, 1.1 to 1.4)309,312,313,343 (Appendix Table F47). The drug had to be given to 12 women to achieve continence in one woman (NNT 12, 95 percent CI, 8 to 25) (Table 7).

Improvement in UI

Tolterodine improved UI more often than placebo88,309,313,454,456,461,463,464 (Appendix Table F47). The drug needed to be given to 10 women to achieve improvement in UI in one (Table 7). The magnitude of the association differed across the studies, probably because of different definitions of improvement. Women’s characteristics, treatment dose and duration, and study quality were not associated with the outcome (Appendix Table F48).

Secondary data analyses demonstrated that 4mg/day of tolterodine, but not 2 mg/day, improved subjects’ perceptions of their bladder condition (Appendix Table F52).87,88,456 Women evaluated treatment success as “much better” more often with 4 mg/day of tolterodine than with placebo456 (Appendix Table F52). One pooled analysis reported a greater decrease in the urgency perception scale score with 4 mg of tolterodine daily than with placebo.456 An evidence-based report about treatment of overactive bladder in women showed a significant decrease in the frequency of UI episodes with immediate release (weighted mean difference 1.45, 95 percent CI, 1.24 to 1.66) and with controlled release tolterodine (weighted mean difference 1.75, 95 percent CI, 1.65 to 1.85).112 One nonrandomized study reported that 79 percent of subjects experience improvement in UI after 12 weeks of tolterodine.470–472

Adverse Effects

Adverse effects were more common with tolterodine than with placebo309,312,321,322,343,449,450,453,457,460,465,477 (Appendix Table F47). Active drugs needed to be given to 12 women in order cause adverse effects in one woman (Table 7). Half of the women experienced adverse effects with 4 mg/day of tolterodine in the IMPACT noncontrolled study.470–472 According to pooled analysis of the aggregate data,309,448,450–452 and one pooled analysis of individual patient data, women did not have serious adverse effects more often with tolterodine than with placebo.87 The same pooled analysis, however, reported that dose reduction in the case of intolerance was more common with 2 mg twice/day of tolterodine than with placebo87 (Appendix Table F52). The rates of all449,453 or serious adverse effects with different doses and formulations of tolterodine did not differ451,452 (Appendix Table F53).

Among individual adverse effects, tolterodine significantly increased rates of autonomic nervous system disorders,448–450 constipation,321,449,451–453,455,457,458,477,478 dyspepsia,309,322,343,451,452,455,457 and fatigue309,460,463 (Table 8). Tolterodine also increased rates of abdominal pain.309,451–453,455,457 Pooled analysis of individual patient data demonstrated greater rates of abdominal pain,456 autonomic nervous system disorder,87 fatigue,88,468 and dry mouth88,456,468 (Appendix Table F52). Autonomic nervous system disorder was less common with 1 mg twice daily versus 2 mg daily.87,448 Differences in adverse effects of different doses and formulations of tolterodine were not consistent across the individual studies and pooled data from individual patients (Appendix Table F53). Tolterodine caused dry mouth in one woman among seven treated according to our pooled analysis (Table 7).309,312,313,321,322,343,451,453,460,461,463,465,477,478 Increases in the rates of dry mouth were not greater with higher doses of tolterodine (p value for meta-regression >0.5).

Clinical Effectiveness of Darifenacin

A high level of evidence indicated significant improvement in urgency UI episodes and several domains of quality of life with 7.5 and 15 mg of darifenacin compared to placebo. Adverse effects were more common with darifenacin than with placebo. Darifenacin increased rates of constipation, dry mouth, dyspepsia, and headache. Darifenacin improved UI in 117 women per 1,000 treated while 190 women per 1,000 treated experienced various adverse effects. Evidence was insufficient from which to conclude better benefits with 30 mg of darifenacin/day. The largest dose, however, resulted in greater rates of adverse effects. Treatment discontinuation rates due to adverse effects were the same between darifenacin and placebo.

Continence

Urinary continence outcomes were not examined with darifenacin treatment. One pooled analysis demonstrated that women did not experience continence for more than 7 consecutive days more often with 15 mg of darifenacin than with placebo486 (Appendix Table F55). The rates of more than 3 dry days/week were greater than placebo with 7.5 mg of darifenacin (RR 1.47, 95 percent CI, 1.02 to 2.13) and with 15 mg of darifenacin (RR 1.48, 95 percent CI, 1.04 to 2.09).486 The drug had to be given to 17 women to achieve 3 dry days/week in one woman.486

Improvement in UI

Darifenacin improved UI more often than placebo479,481,482 (Appendix Table F47). Darifenacin needed to be given to nine women in order to improve UI in one woman (Table 7). Pooled individual patient data from three RCTs also indicated a significant reduction of more than 90 percent in UI episodes more often with 7.5 mg and 15 mg of darifenacin than with placebo486 (Appendix Table F55). Women experienced reductions of more than 50 percent479,481,482 or more than 70 percent479,482 in UI episodes more often with darifenacin than with placebo.

Adverse Effects

Adverse effects were more common with 7.5479,482 and 15 mg/day of darifenacin than with placebo.482,483 Adverse effects were experienced by one woman among every five treated with darifenacin479,482,483 (Table 7). The Darifenacin Study found a significant dose response association with a greater rate of adverse effects with larger doses of darifenacin (Appendix Tables F56 and F57). The rates of serious adverse effects did not differ between darifenacin and placebo.482,483

Rates of individual adverse effects did not demonstrate a consistent dose response association with darifenacin (Appendix Table F57). Among individual adverse effects, darifenacin increased rates of constipation.479,480,482,483,489 The association was not dose responsive because constipation with 15 mg/day did not differ from placebo.480,482,483,489 Dry mouth was more common with 7.5 mg darifenacin than with placebo.479,480,482,483,489 Much less expected was the fact that rates of dry mouth did not differ from placebo, even with larger doses of darifenacin of 15 mg480,482,483,489 or 30 mg/day.482,489 Dyspepsia was more common with darifenacin than with placebo480,482,483,489 (Table 8).

Treatment discontinuation rates483,489 and discontinuation because of adverse effects did not differ between darifenacin and placebo306,307,479,481–483,489 (Table 7). The Darifenacin Study Group reported a significant dose response association with greater rates of withdrawals due to adverse effects with 30 mg than with 7.5 mg of darifenacin/day482 (Appendix Table F57).

Clinical Effectiveness of Solifenacin

A high level of evidence suggested that solifenacin increased continence rates with greater benefits with the larger dose of the drug in women with urgency and mixed UI. Evidence was insufficient that solifenacin improved quality of life. A high level of evidence suggested greater risk of dry mouth, constipation, and blurred vision with the drug. A high level of evidence suggested that 10 mg of solifenacin increased the risk of severe dry mouth and constipation. Treatment discontinuation due to adverse effects was more common with solifenacin than with placebo. Solifenacin resolved UI in 107 women per 1,000 treated, while 13 women per 1,000 treated stopped taking the drug because of adverse effects.

We identified nine publications of individual RCTs477,478,490–496 and pooled analysis of individual patient data from four RCTs497–499 that examined clinical outcomes with solifenacin compared to placebo (Appendix Table F27). We also reviewed the results from the nonrandomized VOLT flexible-dosing trial (VESIcare Open-Label Trial) that examined quality of life in subjects with OAB and urgency UI at 207 centers in the United States.500,501

Continence

Solifenacin resolved UI more often than placebo (pooled RR 1.5, 95 percent CI, 1.4 to 1.6)492,494,496,497,499 (Appendix Table F47). Solifenacin needed to be given to nine women to achieve continence in one woman (Table 7). The effect was consistent across the studies. Complete urinary continence was greater with 10 mg of solifenacin than with placebo in two pooled analyses of individual patient data with a relative increase of 43 percent499 to 53 percent497 (Appendix Table F58). One pooled analysis of individual patient data from four RCTs demonstrated significant dose response increase in continence with better effect with 10 versus 5 mg of solifenacin in women with mixed UI499 (Appendix Table F59). Another previously published pooled analysis of individual patient data, however, did not find better continence rates with the larger dose of the drug in women with urgency UI.497

Improvement in UI

Solifenacin improved UI more often than placebo492,495 (Table 7). The drug needed to be given to six women to achieve improvement in one woman.492,495

Adverse Effects

Adverse effects were more common with solifenacin than with placebo477,494–496 (Table 7). The association was significant but not dose responsive (p value for meta-regression >0.5). Among individual adverse effects, dry mouth was the most common with both doses of solifenacin.477,492–495,497,499,502 Pooled analysis of individual patient data reported significant positive dose response association between dry mouth and the larger dose of the drug497,499 (Appendix Table F59). The larger dose of the drug caused blurred vision and mild blurred vision more often than placebo (Appendix Table F58).497,499 Constipation and severe constipation were more common with 10 mg of solifenacin than with placebo.497,499

Adverse effects leading to discontinuation were more common with solifenacin than with placebo (Table 7).478,493–497,499,502 Every 78th woman discontinued the treatment with solifenacin because of adverse effects. Much less expected was the fact that two pooled analyses of individual patient data demonstrated no difference in treatment discontinuation with 5 or 10 mg of solifenacin than with placebo497,499 (Appendix Table F58). One pooled analysis of individual patient data of four RCTs reported that women with mixed UI stopped treatment because of adverse effects more often with 10 mg of solifenacin than with 5 mg of the drug499 (Appendix Table F59).

Clinical Effectiveness of Fesoterodine

A low level of evidence indicated a significant increase in continence with fesoterodine. A high level of evidence indicated a significant improvement in urgency UI with fesoterodine compared to placebo, with a better response with 8 mg versus 4 mg. Evidence was low that fesoterodine improved quality of life in women with urgency UI. Fesoterodine treatment resulted in higher rates of adverse effects and related discontinuation of treatment than placebo. Adverse effects were more common with 8 mg than with 4 mg of fesoterodine. Women experienced dry mouth and severe dry mouth with fesoterodine more often than with placebo, with a greater risk with the larger dose of the drug. Fesoterodine resolved UI in 130 women per 1,000 treated, while 31 women per 1,000 treated stopped taking the drug because of adverse effects.

Continence

Improvement in UI

Fesoterodine improved UI more often than placebo.309,461,503,505 The drug needed to be given to 10 women to achieve improvement in UI in one (Table 7). One pooled analysis of individual patient data from two RCTs found that the proportion of women indicating that their condition greatly improved or improved was significantly larger with 4 or 8 mg of fesoterodine than with placebo88 (Appendix Table F61). Treatment response was significantly better with the higher dose of the drug88 (Appendix Table F62). An evidence-based report about treatment of OAB in women found a significant reduction in daily UI episodes with fesoterodine (weighted mean difference 2.03, 95 percent CI, 1.74 to 2.31).112

Adverse Effects

Adverse effects were more common with fesoterodine than with placebo (Appendix Table F47).309,460,505,506 One pooled analysis of individual patient data from two RCTs also demonstrated increased rates of adverse effects with fesoterodine than with placebo, showing that the drug given to six to ten women results in adverse effects in one woman.508 The risk of adverse effects was dose responsive with significantly higher rates with 8 mg than with 4 mg of the drug (Appendix Table F62).460,506 Dry mouth was the most common adverse effect with fesoterodine309,313,316,460,461,503,505,506 (Appendix Table F47). An increased risk of dry mouth was dose responsive with greater rates with 8 mg than with 4 mg of the drug460,506,507 (Appendix Table F62).

Among other adverse effects, individual RCTs (Appendix Table F47), pooled analyses of aggregate (Table 7), and pooled analyses of individual patient data (Appendix Table F61),88,468,507 found higher rates of constipation with fesoterodine than with placebo.309,313,316,460,461,503,505,506 Increased risk of urinary tract infection was small but significant with fesoterodine versus placebo in one RCT461 while pooled analysis of individual patient data did not show statistically significant differences in the rates of urinary tract infection between 4 or 8 mg of darifenacin and placebo508 (Appendix Table F63).

Discontinuation due to adverse effects was more common with fesoterodine than with placebo309,313,316,461,503,505 (Appendix Table F47). The drug given to 33 women resulted in discontinuation of treatment due to adverse effects in one woman (Table 7). One pooled analysis of individual patient data from two RCTs507 examined withdrawal rates due to adverse effects with fesoterodine and placebo (Appendix Table F61). Discontinuation rates due to adverse effects did not differ between 4 mg of fesoterodine and placebo but were significantly higher with 8 mg of darifenacin than with placebo.507

Clinical Effectiveness of Trospium

A high level of evidence indicated increased continence rates with trospium compared to placebo. Individual RCTs found that trospium improved quality of life. Women experienced dry mouth, dry eye, dry skin, and constipation more often with the drug than with placebo. Adverse effects resulted in treatment discontinuation with the drug more often than with placebo. Trospium resolved UI in 114 women per 1,000 treated, while 18 women per 1,000 treated stopped taking the drug because of adverse effects.

Eight publications of RCTs,308,325,329,330,509–512 two publications of the Trospium Study Group,513,514 and one pooled analysis of individual patient data from two RCTs512 examined the effects of trospium on clinical outcomes compared to placebo (Appendix Table F27).

Continence

Trospium increased continence rates more often than placebo325,512–514 (Appendix Table F47). The drug needed to be given to nine women to achieve continence in one woman515 (Table 7). Trospium increased rates of a complete response defined as continence and normal voiding in a pooled analysis of individual subject data from two RCTs.515 The drug had to be given to 11 women (95 percent CI, 8 to 20) to achieve complete response in one woman.515

Improvement in UI

Trospium improved UI more often than placebo.509,513 The Trospium Study Group demonstrated a significant improvement in UI, defined as a greater than 50 percent decrease in the number of incontinent episodes per 24 hours.513

An evidence-based report about treatments for overactive bladder in women demonstrated a significant reduction in urgency UI by 2.45 episodes per day (mean difference 2.45, 95 percent CI, 2.19 to 2.7).112

Women using trospium experienced dry eye,512,514 dry mouth,325,465,510,512–514 and dry skin512,514 more often than those using a placebo.515 The most common adverse effect was dry mouth, experienced by one woman of every nine treated (Table 7). Discontinuation rates due to adverse effects were also higher with trospium than with placebo329,330,510,512–514 (Table 7).

Clinical Effectiveness of Propiverine

A low level of evidence indicated that propiverine resolved UI. A moderate level of evidence indicated that propiverine improved urgency UI and increased the risk of adverse effects, including abnormal vision, constipation, and dry mouth in a dose responsive manner. Propiverine resolved UI in 163 women per 1,000 treated, while 34 women per 1,000 treated stopped taking the drug because of adverse effects.

Continence

Propiverine increased continence rates more often than placebo320,516 (Appendix Table F47). The drug had to be given to six women to achieve continence in one. One study concluded higher rates of continence with immediate-than with extended-release propiverine (RR 1.3, 95 percent CI, 1.1 to 1.6).320

Improvement in UI

Propiverine improved UI more often than placebo320,516,518 (Appendix Table F47). The drug was effective in resolving symptoms of urgency but not UI in older women with mixed UI (Appendix Table F64).516 One study compared immediate- versus extended-release propiverine and concluded an opposite association depending on the definition of improvement.320 Investigators rated better overall efficacy with the extended-release drug. In contrast, patients reported better overall efficacy with the immediate-release drug.320

Adverse Effects

Propiverine caused adverse effects more often than placebo320,517,518 (Appendix Table F47). Propiverine caused adverse effects in one woman of every six treated. Rates of adverse effects were relatively higher with 20 mg of propiverine and 45 mg/day of propiverine than with placebo.517 Treatment discontinuation due to adverse effects was more common with propiverine than with placebo320,502 (Appendix Table F47).

Clinical Effectiveness of Botulinum Toxin

A high level of evidence suggested a reduction in UI episodes due to treatment with botulinum toxin, with an increased risk of elevated post-void residual in patients with severe urgency UI refractory to antimuscarinic drugs.

Four RCTs of 185 subjects reported clinical outcomes after intravesicular injection of botulinum toxin315,519–521 (Appendix Table F27). We found one systematic review of the literature about the efficacy and safety of botulinum toxin in the management of OAB.522

Continence

Two RCTs demonstrated that botulinum injections resolved urgency UI. A single published RCT randomized 313 adults with idiopathic OAB and daily urgency UI to placebo or different doses of botulinum toxin.523 The outcomes were compared after intradetrusor injections of 50, 100, 150, 200, or 300 U of botulinum toxin or placebo.523 Continence rates were greater with the active drug (29.8 to 57.1 percent) than with placebo (15.9 percent, P <0.5) in a dose responsive fashion.523 One unpublished RCT315 demonstrated a significant increase in continence after a single injection of 100U to 300U of botulinum toxin.

Improvement in UI

One RCT reported greater rates of significant improvement in UI (>75 percent decrease in daily UI episodes) with botulinum toxin than with placebo520 (Appendix Table F65). Recently published RCTs examined different doses of the drug and demonstrated minimal additional or clinically relevant improvement in symptoms with doses higher than 150 U.523 One RCT reported improvement in several domains in King’s Health Questionnaire on quality of life after botulinum toxin compared to placebo519 (Appendix Table F66). The differences were small but statistically significant for UI impact, severity measure, and sleep-energy disturbances.519

Published RCTs found that the drug caused treatment-related adverse effects in 40 percent, and post-void residual (PVR) related catheterization in 20 percent of patients.523 The rates of urinary tract infection increased in a dose responsive manner from 37 percent with 100 U to 47.2 percent with 300 U.523 The rates of urinary retention also increased in a dose responsive manner from 19 percent with 100 U to 25 percent with 300 U.523 Treatment failure with unchanged or increased UI was less common with botulinum than with placebo (RR 0.29, 95 percent CI, 0.14 to 0.63).520

Clinical Effectiveness of Resiniferatoxin

Evidence on the benefits and harms of resiniferatoxin versus placebo in women with urgency UI was insufficient for definitive conclusion about benefits and harms with the drug.

A single RCT enrolled 58 women with idiopathic detrusor overactivity and urgency incontinence to examine clinical outcomes of resiniferatoxin versus placebo (Appendix Table F27).524 The study did not demonstrate benefits of resiniferatoxin versus placebo524 (Appendix Table F67). The rates of the expected adverse effects, including hypogastric pain, dysuria, and minor hematuria, did not differ between resiniferatoxin and placebo.524

Clinical Effectiveness of Nimodipine

Evidence was insufficient for the benefits or harms of nimodipine compared to placebo in older women with predominant urgency UI.

A single RCT enrolled 86 older adult women with urodynamic urgency UI and without clinically important stress UI to examine outcomes after 3 weeks of 30 mg nimodipine twice daily or placebo525 (Appendix Table F27). Nimodipine reduced incontinent episodes but did not improve IIQ scores and American Urological Association symptom scores (Appendix Table F68). Treatment discontinuation did not differ between nimodipine and placebo.525

Comparative Effectiveness of Pharmacological Treatments

Comparative Effectiveness of Topical Estrogen on Stress UI

Evidence was insufficient to determine whether an estrogen releasing intravaginal ring was more effective in resolving and improving UI than a pessary or to determine whether an intravaginal tablet was more effective than intravaginal estrogen cream (Appendix Table F69).

Two RCTs of 291 women compared different estrogen formulations (Appendix Table F27).526,527 The studies enrolled postmenopausal women with lower urinary tract symptoms including UI.526,527 The first study compared an intravaginal tablet with intravaginal conjugated estrogen cream administered for 8 weeks.526 The second study compared an estrogen releasing ring with an estrogen pessary administered for 24 weeks.527 Continence rates did not differ between the intravaginal tablet and the intravaginal cream526 (Appendix Table F70). Women treated with an estrogen releasing ring did not experience urgency UI more often than those treated with a pessary.527 The rates of resolved stress UI did not differ between estrogen rings and pessaries.527 Women were satisfied with the estrogen ring more often than with the estrogen pessary.527

An estradiol vaginal ring and oral oxybutynin demonstrated similar effects in decreasing the number of daily voids in postmenopausal women with overactive bladder.528 Quality of life score did not differ with two drugs.528 Women experienced constipation and dry mouth more often with oxybutynin than with an estrogen ring.528 Bothersome adverse effects leading to treatment discontinuation did not differ between the drugs.528

Comparative Effectiveness of Darifenacin and Oxybutynin on Urgency UI

Evidence was insufficient from which to conclude comparative effectiveness between darifenacin and oxybutynin on continence or improved UI. A low level of evidence indicated lower rates of total adverse effects and dry mouth with darifenacin, with no differences in adverse effects leading to treatment discontinuation.

Continence

Improvement in UI

The studies found no differences in improvement of UI between the two drugs. Both drugs significantly reduced incontinence episodes compared to placebo, with no differences between drugs.446

Adverse Effects

Darifenacin was safer than oxybutynin. Total rates of adverse effects were lower with darifenacin than with oxybutynin529 (Appendix Table F71). Rates of dry mouth were lower with darifenacin than oxybutynin.446 Severe dry mouth was less common with 7.5 mg/day of darifenacin than with 7.5mg/day of oxybutynin, and lower with 15 mg/day of darifenacin than with 15 mg/day of oxybutynin529 (Appendix Table F72). Only one adverse effect, constipation, was more common with 30 mg of darifenacin than with 15 mg of oxybutynin529 (Appendix Table F73). Discontinuations from the study due to treatment-related adverse effects were lower with darifenacin than with oxybutynin in one RCT446 (Appendix Table F74). Pooled analysis of two RCTs found no significant differences between the two drugs in adverse effects leading to treatment discontinuation (Table 9).

Discontinuation due to adverse effects with pharmacological treatments for urgency UI (pooled with random effects estimates from head-to-head RCTs).

Comparative Effectiveness of Oxybutynin and Tolterodine on Urgency UI

Evidence was insufficient from which to draw conclusions about comparative effectiveness between oxybutynin and tolterodine on continence. A moderate level of evidence indicated no difference between the drugs for UI improvement. A high level of evidence indicated more frequent treatment discontinuation due to adverse effects with oxybutynin than with tolterodine. Women experienced dry mouth and several other adverse effects more often with oxybutynin than with tolterodine. Thus, the drugs offered equal benefits, but tolterodine resulted in fewer harms.

Continence

Urinary continence was reported in the OPERA trial of 790 women.533 Ten mg/day of oxybutynin, compared to 4mg/day of tolterodine, resulted in greater rates of continence533 (Appendix Table F75). Drugs had to be given to 16 women to achieve continence in one (Table 10).

Improvement in UI

We found no difference between the two drugs322,441,531 (Figure 5). Treatment-related rates of improved bladder condition did not differ between the two drugs in a pooled analysis of individual patient data from four RCTs87(Appendix Table F76).

Adverse Effects

Tolterodine demonstrated better safety than oxybutynin in several individual RCTs and secondary data analyses (Appendix Table F71). Total adverse effects did not differ between the drugs according to the pooled aggregate data from the published studies.450,531,532 However, one pooled analysis of individual patient data from four RCTs demonstrated higher rates of moderate and severe adverse effects with 10 mg/day of oxybutynin compared to 4 mg/day of extended-release tolterodine536 (Appendix Table F77). Even though another pooled analysis of individual patient data from four RCTs found no differences in serious adverse effects between oxybutynin and tolterodine, dose reduction rates due to intolerance were more common with oxybutynin than with tolterodine.87

Among individual adverse effects, dry mouth was more common with oxybutynin than with tolterodine441,442,450,530,531,533,534 (Figure 5). Severe dry mouth was also more common with 5 mg/day of oxybutynin than with 2mg/day or 1mg/day of tolterodine.87 In addition to dry mouth, women experienced asthenia,536 autonomic nervous system disorder,87 gastrointestinal disorders,87 dyspepsia,87 nausea,536 pain,536 palpitations,87 rhinitis,536 and urinary tract infections536 more often with oxybutynin than with tolterodine.

Comparative Effectiveness of Propiverine and Oxybutynin on Urgency UI

Improvement in UI and subject satisfaction did not differ between the two drugs (Appendix Table F76). Total adverse effects did not differ between the two drugs (Appendix Table F71). Fewer subjects experienced severe dry mouth with propiverine than with oxybutynin.439 No studies compared rates of treatment discontinuation due to adverse effects between the two drugs.

Comparative Effectiveness of Flavoxate and Oxybutynin on Urgency UI

Evidence was insufficient from which to draw conclusions about comparative effectiveness and safety of flavoxate and oxybutynin.

A single RCT of 100 subjects compared clinical outcomes of 1,200 mg/day of flavoxate hydrochloride and 15mg/day of oxybutynin.538 Neither urinary continence nor improvement in UI differed between the two drugs538 (Appendix Tables F75 and F76). Neither treatment failure with worsening of UI nor total number of adverse effects differed between the two drugs.538 Rates of dry mouth and dry eyes were significantly lower with flavoxate than with oxybutynin. Nausea was also significantly less common with flavoxate than with oxybutynin.538

Comparative Effectiveness of Tolterodine and Propiverine on Urgency UI

Evidence was insufficient from which to draw conclusions about comparative effectiveness and safety of propiverine and tolterodine.

We identified one RCT of 202 patients treated with 15 mg of propiverine twice daily or 2 mg of tolterodine twice daily.539 No studies compared continence and improvement in UI with the two drugs.539 Improvement in urodynamic criteria of detrusor overactivity did not differ between the two drugs.539 Both drugs improved quality of life scores without significant differences between them. The rates of total adverse effects did not differ between the two drugs (Appendix Table F71).

Comparative Effectiveness of Tolterodine and Fesoterodine on Urgency UI

A low level of evidence indicated greater continence rates with fesoterodine than with tolterodine. A high level of evidence indicated greater rates of improvement in UI with fesoterodine than with tolterodine. A moderate level of evidence indicated higher rates of adverse effects that led to treatment discontinuation with fesoterodine than with tolterodine.

Continence

Improvement in UI

Rates of improvement in UI were greater with fesoterodine.88,309,313,461 Pooled analysis of individual patient data from two RCTs that included 1,548 women analyzed self-rated substantial benefits from the treatments88 and found no difference in the rates of this outcome between fesoterodine and tolterodine (Appendix Table F78).

Quality of life did not differ between fesoterodine (4 or 8 mg) and tolterodine extended release in pooled analysis of individual subject data from two RCTs.540

Adverse Effects

Rates of total adverse effects did not differ between 4 mg of tolterodine and 4 mg of fesoterodine, but were less with tolterodine than with 8 mg of fesoterodine.460 Rates of dry mouth were less with tolterodine than with 4 mg of fesoterodine. Pooled analysis of individual patient data from two RCTs found that dry mouth was less common in women treated with tolterodine than with 8 mg/day of fesoterodine, with no significant differences when compared to 4 mg of fesoterodine.88 Urinary tract infection was also less common in women treated with tolterodine than with 8 mg/day of fesoterodine, with no significant differences compared to 4 mg of fesoterodine.88

Comparative Effectiveness of Solifenacin and Tolterodine on Urgency UI

Comparative effectiveness evidence was insufficient for solifenacin and tolterodine. A moderate level of evidence indicated that adverse effects leading to treatment discontinuation did not differ between the two drugs.

Six publications of RCTs compared clinical outcomes of solifenacin and tolterodine,114,477,478,541–543 including the Solifenacin and Tolterodine as an Active comparator in a Randomized STAR study group that compared clinical outcomes of 5 or 10 mg of solifenacin and 4 mg of extended-release tolterodine.541,542 The studies examined different doses of the drugs on a variety of outcomes that hampered the synthesis of evidence.

Improvement in UI

Adverse Effects

Total rates of adverse effects did not differ between solifenacin and tolterodine114,477 (Appendix Table F71). However, one published RCT demonstrated a significant increase in adverse effects with the highest dose of solifenacin (20mg once daily) compared to tolterodine. A lower dose of solifenacin resulted in the same rates of adverse effects as tolterodine in one published477 and one unpublished RCT.114 Dry mouth and constipation were more common in women treated with solifenacin than with tolterodine.542 Blurred vision was less common with solifenacin than with tolterodine542 (Appendix Table F80).

Treatment discontinuation rates due to adverse effects did not differ between the two drugs.114,478,542,543

Comparative Effectiveness of Solifenacin and Darifenacin on Urgency UI

Evidence was insufficient from which to conclude comparative effectiveness and safety of solifenacin and darifenacin.

The Solidair study found that women taking solifenacin had to increase the dose of the drug more often than women taking darifenacin.544 The Solidair study found that the rates of treatment discontinuation due to adverse effects did not differ between solifenacin and darifenacin.

Comparative Effectiveness of Solifenacin and Oxybutynin on Urgency UI

Evidence was insufficient from which to conclude comparative effectiveness and safety of solifenacinoxybutynin.

A single RCT, the VECTOR trial, compared 5 mg solifenacin once daily versus 5 mg oxybutynin immediate release three times daily.545 Both drugs improved results in the Patient Perception of Bladder Condition scale and Overactive Bladder Questionnaire, without evident differences between them.

Rates of adverse effects were lower with solifenacin than with oxybutynin.545 Dry mouth was less common with solifenacin than with oxybutynin.545 Rates of dry mouth leading to treatment discontinuation were lower with solifenacin than with oxybutynin.545 Rates of other adverse effects resulting in treatment discontinuation did not differ between the two drugs.545

Comparative Effectiveness of Solifenacin and Propiverine on Urgency UI

Evidence was insufficient from which to conclude comparative effectiveness and safety of solifenacin and propiverine.

A single RCT compared clinical outcomes of solifenacin and propiverine.502

This study reported a significant reduction in UI episodes with both drugs, without significant differences between them.502

The rates of dry mouth did not differ between 5mg/day of solifenacin and propiverine.502

Adverse effects leading to treatment discontinuation did not differ between the two drugs.

Comparative Effectiveness of Trospium and Oxybutynin on Urgency UI

Evidence was insufficient from which to conclude comparative effectiveness between trospium and oxybutynin. Individual studies found lower rates of dry mouth with trospium than with oxybutynin. A low level of evidence indicated no differences in treatment discontinuation due to adverse effects between the two drugs.

Continence

Improvement in UI

One RCT compared improvement in UI with oxybutynin and trospium and did not find significant differences305 (Appendix Table F76). Dose escalation of either trospium or oxybutynin reduced frequency of urge UI without statistically significant differences between the two drugs.547

Adverse Effects

Trospium was better tolerated with fewer adverse effects than oxybutynin546 (Appendix Table F71). Dry mouth was less common with trospium than with oxybutynin546 (Appendix Table F72). With dose escalation, worsening of dry mouth was lower in the trospium groups than in the oxybutynin groups.547 Treatment discontinuation due to adverse effects did not differ between the two drugs305,546 (Table 9).

Comparative Effectiveness of Trospium and Tolterodine on Urgency UI

Evidence was insufficient from which to conclude the comparative effectiveness and safety of trospium and tolterodine.

Indirect evidence did not indicate substantial differences in resolving or improving UI with different drugs. Differences in discontinuation due to adverse effects, including dry mouth, were more evident than differences in benefits. However, head-to-head comparisons were rarely available in more than one study, and the studies used different definitions of treatment success and different tools to measure quality of life.

We compared relative benefits and harms of drugs compared to placebo. Such indirect evidence from all RCTs that examined clinical outcomes of active drugs versus placebo indicated that trospium was the most effective to resolve UI (Figure 6), but the differences across the drugs were not significant. Absolute rates of continence were the highest with solifenacin and fesoterodine (Figure 7). Indirect statistical comparisons were difficult because of substantial variability in continence rates with placebo. For instance, women became continent with placebo in RCTs of fesoterodine (48 percent), oxybutynin (16 percent), solifenacin (28 percent), tolterodine (44 percent), and trospium (17 percent).

We analyzed which factors might contribute to such differences in continence with placebo. The studies that did not report whether they included cases of mixed incontinence had lower rates of continence with placebo (18 percent) than studies that excluded women with stress UI (30 percent). The studies that included women with severe daily UI reported higher rates of continence with placebo (28 percent) than the studies that omitted baseline daily frequency of UI (15 percent).

From quality criteria of the studies, masking of treatment would be the most obvious candidate to explain continence with placebo. All drug studies that examined continence, however, were double blinded. From other quality criteria, the studies that reported justification of the sample size had higher continence with placebo (28 percent) than the studies that did not justify sample size (17 percent). Considering substantial variability in continence rates with drugs and placebo, but comparable relative effectiveness of the drugs, comparative safety of the drugs may influence decisions on which drug offers a better balance between benefits and harms.

Compared to placebo, all drugs except darifenacin and tolterodine led to more treatment discontinuation due to adverse effects. The number needed to treated was the highest with solifenacin (NNT=78) and the lowest with oxybutynin (NNT=16). The absolute rates of adverse effects leading to treatment discontinuation were the highest with oxybutynin, and were comparable between other drugs (Figure 8). Dry mouth was the most common adverse effect (Figure 9). Rates of dry mouth were the highest with oxybutynin. Among other adverse effects, constipation and blurred vision were the most common (Figure 10).

Discontinuation of treatments due to adverse effects (%) with drugs vs. placebo (pooled results from RCTs). Vertical axis = percentage of those who discontinued treatments due to adverse effects Horizontal axis = treatments with drug or placebo

Rates (%) of the most common (>10%) adverse effects with drugs vs. placebo (pooled results from RCTs). Horizontal axis = percentage of subjects with adverse effects

Indirect comparisons indicated comparable effectiveness of the drugs on continence. Oxybutynin had higher rates of dry mouth and treatment discontinuation due to adverse effects than other drugs.

Several retrospective observational studies analyzed comparative effectiveness and safety of pharmacological treatments for UI. The evidence-based cost utility analysis reported that more than half of patients stop taking drugs for UI after 1 year of treatment (Figure 11).548 The lowest rates of treatment discontinuation were with 5 mg of solifenacin.548 The authors estimated quality adjusted life years using treatment response rates and discontinuation rates for all drugs and demonstrated the largest gain in quality adjusted life years per 1,000 treated with solifenacin (Figure 12). Trospium, which demonstrated the highest continence rates, was not included in this analysis (Appendix Figure F26).

Clinical outcomes with duloxetine vs. placebo in age subgroups (pooled analysis of individual data on women from four RCTs). PGI-I = Patient Global Impression of Improvement

The Role of Patient Characteristics on Patient Outcomes With Pharmacological Treatments

Age

The rates of clinical outcomes were similar in age subgroups. Clinical outcomes in age subgroups were reported in four studies involving duloxetine,398solifenacin,497tolterodine,314 and oxybutynin.314,398,497,534 Active and control treatments, outcomes, and definitions of age subgroups varied across the studies. We describe clinical outcomes in age subgroups treated with the drugs from individual studies and pooled analyses of individual subject data.

In 1,913 women ages 22 to 83 years with predominant stress UI, duloxetine compared to placebo did not improve UI in older women (Figure 12).398

In contrast, younger women reported improvement in UI more often with duloxetine than with placebo.398 Duloxetine prevented worsening of UI in older women, but was not better than placebo in women younger than 50 years of age.398

Solifenacin increased continence rates more often than placebo in all age groups (Figure 13).497 The drug tended to benefit older women more than younger women. For instance, the relative increase in continence with 5 mg was 38 percent in younger and 69 percent in older individuals.497 We observed the same tendency with 10 mg of solifenacin, with a relative increase in continence of 49 percent in younger people and of 63 percent in older people.497 This tendency was not statistically significant.

Oxybutynin reduced the number of urgency and total UI episodes more often than tolterodine in women younger than 64 years with urgency or mixed UI in one RCT.534 The rates of adverse effects did not differ between age groups.

Several studies did not directly compare the outcomes among treatment groups but aimed to test treatment effects in older populations. Oxybutynin, trospium, and darifenacin improved UI in older women. Oxybutynin reduced UI frequency and produced subjective benefits compared to placebo in frail community-dwelling older people.406 Darifenacin was examined in older populations in two RCTs479,480 and one pooled analysis of three RCTs.487 Darifenacin resulted in improvement in UI when compared to placebo in the older women.479 The drug needed to be given to eight older patients to achieve more than a 50 percent reduction in UI episodes in one person. Cognitive function changes did not differ between darifenacin and placebo in short-term (2-week) treatment.480 Dry mouth, constipation, and dyspepsia were the most common adverse effects in the older subjects.

Evidence suggested that age did not modify the effects of the tested drugs on examined clinical outcomes. Trospium was effective improving UI and quality of life in older subjects with overactive bladder.549 A high level of evidence suggested that duloxetine was no better than a placebo in improving UI in older women. A high level of evidence suggested that solifenacin increased continence rates more often than placebo, regardless of age. Oxybutynin, trospium, and darifenacin improved UI in older women.

Race

Evidence was inconclusive about differences among racial groups in the effects of duloxetine for stress UI. Only one study, DESIRE (Duloxetine Efficacy and Safety for Incontinence in Racial and Ethnic Populations) examined clinical outcomes in different race groups.388 Women with stress UI were treated with 80 mg of duloxetine per day. Weekly UI episodes were reduced compared to baseline in all race groups, by 65.7 percent in African Americans, by 73.0 percent in Hispanics, and by 75.0 percent in Caucasian women. Clinical outcomes rarely differed between racial subgroups (Figure 15).388 African American women reported improvement in UI more often than Caucasian women. Hispanic women experienced a reduction in UI by more than 50 percent less often than Caucasian women. Several adverse effects, including dizziness, headache, and somnolence, were less common among African American women and more common among Hispanic women than among Caucasian women. The biological plausibility of such differences is not clear.

Clinical outcomes with duloxetine in racial subgroups of women with stress UI, DESIRE (Duloxetine Efficacy and Safety for Incontinence in Racial and Ethnic populations).

Baseline Type of UI

Evidence was not sufficient for individualized prediction of benefits by the urodynamic type of UI.

The studies of antimuscarinic drugs enrolled subjects with overactive bladder and predominant urgency UI. The studies of duloxetine enrolled subjects with predominant stress UI. Few studies compared the outcomes in subgroups with the predominant type of UI. One RCT of tolterodine compared continence rates, reduction in UI episodes, and pad utilization in subjects with predominant urgency and pure urgency UI, and concluded the same treatment benefits in all subjects regardless of the type of UI.469 Two pooled analyses of individual patient data compared clinical outcomes between 5 or 10 mg of solifenacin and placebo.497,498

Both doses of solifenacin increased continence rates compared to placebo. Solifenacin increased continence rates in subjects with pure urgency and mixed UI. The effect size did not differ between subgroups with different types of UI (Figure 16). The relative increase in continence rates was greater with 5 mg of solifenacin in patients with pure urgency UI than those with mixed UI. One pooled analysis demonstrated that 5 mg of solifenacin was not better than placebo in achieving continence in subjects with mixed UI.498 Individuals with mixed UI required longer treatment duration to achieve greater benefits from solifenacin. At the end of 40 weeks of treatment, 52 percent of the people with mixed UI reported regaining continence, and 34 percent reported resolution of symptomatic urgency on uncontrolled extension in one RCT.499

Continence with solifenacin compared to placebo in patients with mixed or pure urgency UI (pooled analyses of individual patient data).

Clinical outcomes of tolterodine and solifenacin did not differ in individuals with baseline mixed or pure urgency UI. Individuals with mixed UI may require a larger dose and longer treatment than women with urgency UI to achieve clinical benefits from solifenacin.

Baseline Frequency of UI

The baseline frequency of UI demonstrated no significant or consistent association with clinical outcomes of any drug. Individuals with more frequent UI had slightly greater benefits with drugs than with placebo. Variability in definitions of baseline severity and clinical outcomes lowered the level of evidence.

Three secondary data analyses of drug trials examined clinical outcomes among subgroups with different baseline frequency of UI.467,497,508 The results indicated that baseline frequency of UI tended to modify the treatment effects of the drugs; however, statistical significance of such modifications was not consistent across the definitions of baseline severity, drugs, and treatment outcomes.

Several drugs resulted in greater benefits for patients with more frequent baseline UI. In a post hoc analysis of an RCT, tolterodine extended-release increased continence rates compared to placebo in patients with symptoms of urinary frequency and pure urgency UI. Urinary continence rates varied by diary-recorded duration and frequency of UI at baseline (Figure 17).467 Individuals with more frequent baseline UI had a larger relative benefit with the drug than with placebo. Five or 10 mg of solifenacin per day increased the rates of continence regardless of baseline frequency of UI in a pooled analysis of 1,873 people with OAB.497 Those with more than three episodes of urgency UI per day at baseline experienced a slightly larger relative benefit than those with less frequent UI.497 Patients with more than two urgency UI episodes per day experienced a greater reduction in the number of urgency UI episodes with 8 mg of fesoterodine in a pooled analysis of two RCTs.508 In contrast, trospium was better than placebo at resolving UI only in subjects with fewer than five UI episodes/day.550 Trospium did not resolve UI in subgroups with more than five episodes of UI/day.550

Adverse effects of fesoterodine compared to placebo in subgroups with different baseline frequency of urgency UI (pooled analysis of four RCTs).

Prior Treatment Status

Solifenacin was effective regardless of the response to previous treatments, even though poor responders did not benefit from increasing the dose of the drug (high level of evidence). One study reported that darifenacin was effective in those for whom previous treatments failed. Tolterodine was no better than placebo in achieving clinical benefits among poor responders to the previous muscarinic antagonists in one RCT.

Many studies reported prior treatment status, but very few reported clinical outcomes in subgroups by the response to previous treatments. In a pooled analysis of individual patient data from four RCTs, solifenacin increased continence rates when compared to placebo, regardless of the response to previous treatments (Figure 19).497 Previous nonresponders experienced a greater relative benefit than those who responded to previous treatments.497 Patients who did not respond to previous treatments did not benefit from increasing the dose of solifenacin.497 Post hoc analysis of the OPERA trial demonstrated greater rates of continence with oxybutynin than with tolterodine in patients with prior treatments with antimuscarinic drugs, but no difference was demonstrated between the two drugs in treatment of naïve patients.551 In one RCT, tolterodine was not better than placebo among poor responders to the previous muscarinic antagonists.453

Concomitant Treatments

Trospium reduced the number of urgency UI episodes irrespective of concomitant medications. Adverse effects were more common in those taking seven or more concomitant medications.552

Comorbidities

Duloxetine was no better than placebo in women with stress UI and comorbidities (one RCT).

One RCT examined clinical outcomes with duloxetine compared to placebo in women with comorbidities (Figure 20).398 Duloxetine was not better than placebo in women with depression, diabetes, and chronic lung diseases, nor was it better than placebo in preventing worsening of UI in underweight women and women with depression, diabetes, and chronic lung diseases.398

Patient global impression of improvement rating as “better” with duloxetine when compared to placebo in subgroups with different comorbidity status (duloxetine urinary incontinence study group).

Obesity

Baseline obesity did not modify the effect of trospium in pooled analysis of individual patient data from RCTs (Table 11).553 Trospium was more effective than placebo in achieving continence in obese and nonobese adults.553 The magnitude of the benefit was similarly low in subgroups with different baseline body mass index (BMI). Trospium resolved urgency UI in 140 per 1,000 treated adults with normal weight or obesity.

Continence with 60 mg once daily of trospium vs. placebo in obese and nonobese adults with overactive bladder (pooled results from RCTs using the WHO criteria for obesity).

Key Question 3. How effective is the nonpharmacological treatment of UI?

One hundred forty eight RCTs tested nonsurgical nonpharmacological treatments for UI (Appendix Table F81). A small proportion of RCTs reported sponsorship and conflict of interest (Appendix Table F82). Sample size was justified in 63 RCTs (43 percent) (Appendix Table F83). Quality of the studies, including intention to treat principle and adequacy of allocation concealment, did not demonstrate significant modification of the association between treatments and patient outcomes (Appendix Table F84). In addition, we reviewed five RCTs that examined eligible treatments for female UI, but did not report the rates of clinical outcomes that can be reproduced and synthesized (Appendix Table F85). We also reviewed the results from 45 nonrandomized studies that reported crude rates of outcomes with medical devices that have never been tested in RCTs (Appendix Table F26). Here, we review clinical effects of nonpharmacological treatments compared to regular care or no active treatment. The majority of the trials included women with mixed UI. We examined the effects of predominantly stress or urgency UI when reported by the authors (Appendix Table F86).

Efficacy of Nonpharmacological Treatments for Stress UI

Clinical Effects of Pelvic Floor Muscle Training (PFMT)

A high level of evidence indicated significant benefits from PFMT for women with UI. Compared to regular care, PFMT increased urinary continence rates and improvement in UI. Benefits were consistent across different regimens of training and definitions of improvement in UI.

Improvement in UI

The majority of the studies also demonstrated a significant benefit from PFMT on improvement of UI (Appendix Table F87).555–557,560,563,564 Women reported improvement in UI with PFMT more often than with regular care.555–557,560,563,564 PFMT improved UI in one of every two women treated. Improvement rates did not differ in the studies with pure stress, mixed, or unreported types of UI.

Quality of life improved after PFMT555,559 (Appendix Table F88). Women expressed improvement in psychological impact of UI and in activity restrictions,555 less overall interference of UI with life, fewer problems with painful intercourse and other interactions of UI with sexual life, and less dissatisfaction from spending the rest of their lives with their present symptoms.559 Several studies reported inconsistent improvement in scores of quality of life after PFMT when compared to no active treatment559,560,565–567 (Appendix Table F89).

Clinical Effects of Vaginal Cones and Pessaries

Evidence was insufficient to draw valid conclusions about the benefits of vaginal cones. Two RCTs compared clinical outcomes with vaginal cones and no active treatment558,563 (Appendix Table F81). One study treated women with clinical and urodynamic stress UI with vaginal cones of 20, 40, and 70g for 20 minutes per day.558 Another study examined nine cones of equal shape and volume, increasing in weight from 20 to 100g.563

Continence rates varied from 36 percent among women with urgency UI to 47 percent among those with stress UI after using Pessary Uresta/EastMed Inc.574 More than half the women (53 percent) reported improvement.574 Among women who used the pessary ring with floor45 percent reported improved stress UI, and 21 percent reported improved urgency UI; however, 6 percent reported newly developed urgency UI.573 Discontinuation rates varied from 11 percent571 after different pessaries to 34 percent574 after Pessary Uresta/EastMed Inc, and to 47 percent after Pessary Gelhorn.572 Unsuccessful fitting was the most commonly reported reason for discontinuation.

Continence

PFMT with biofeedback increased urinary continence in both RCTs that reported this outcome557,560 (Appendix Table F92). Overall, continence rates were significantly greater with active treatment than with usual care.557,560 Increase in continence was greater in the study of pure stress UI560 than of mixed UI.557 Pooled absolute risk difference was not significant, however.557,560

Improvement in UI

PFMT with biofeedback improved UI.440,556,557,560 On average, three women needed to be treated to achieve UI improvement in one (Table 10). The study of weekly sessions of PFMT reported larger improvement in UI.556,557 One study reported impact from UI, finding a small significant improvement on the Social Activity Index560 (Appendix Table F93). One of four studies560 included women with pure stress UI and found no significant improvement in UI. Improvement was consistent in studies of mixed UI.

One study examined the effects of PFMT supervised weekly by skilled physical therapists in women with pure urodynamic stress UI558 (Appendix Table F94). The study reported a large and significant increase in continence (RR 13.24, 95 percent CI, 1.83 to 95.63).558 The treatment had to be provided to three women to achieve continence in one. The same study reported a small but significant improvement in the Leakage Index and in the Social Activity Index (Appendix Table F95).

One noncontrolled study examined the effects of pelvic fitness and education classes taught by a lay instructor to women with urgency UI.576 The training improved quality of life and sexual function measured with Urogenital Distress Inventory-Short Form (UDI-SF) scores. Achievement of self-selected goals was reported by 71 percent at 11 weeks and by 67 percent at 1 year of followup. Evidence was insufficient to draw valid conclusions that PFMT performed under the supervision of nonmedical instructors may improve continence or quality of life in women with UI.

Clinical Effects of Electrical Stimulation

A high level of evidence suggests increased continence rates and improvement in UI with electrical stimulation.

Nine studies examined intravaginal electrical stimulation.558,577–584 The studies included women with predominant urgency UI,581,583 clinical579,580 or urodynamic stress UI,558,577 or urodynamic mixed UI578 (Appendix Table F81). Few studies excluded women with detrusor overactivity.577,579 Electrical stimulation was described with different levels of detail and had variable stimulation parameters, depending on the UI type being treated, including the use of 4 Hz,583 10 Hz,581 20 Hz,578 or 50 Hz558,579,580 frequency for 4 weeks,558,581 7 to 8 weeks,578,583 12 weeks,579 or 15 weeks.577

Continence

Electrical stimulation increased continence rates more often than sham stimulation (Appendix Table F96).558,563,577,579–581,584 The benefit was consistent across the studies, despite differences in women and treatment characteristics. One RCT reported significantly higher rates of continence with electrical stimulation.584 Increase in continence did not differ across the studies with mixed versus pure stress UI. Electrical stimulation needed to be administered in nine women to achieve continence in one (Table 12).

Improvement in UI

Electrical stimulation improved UI in pooled analysis of RCTs558,563,577–581,583 (Appendix Table F97). Benefit was consistent across the studies, despite differences in women and treatment characteristics, and mixed versus pure stress UI (heterogeneity was not significant). Electrical stimulation needed to be administered in six women to improve UI in one woman (Appendix Table F97).

Improvement in UI was also demonstrated in a large prospective cohort study of 3,198 women treated with home-managed vaginal/anal stimulators (20–50 Hz) for at least 3 months before evaluation of the effect585 (Appendix Table F26). Women experienced daily urine loss, substantial urine loss, and severe UI less often with treatment when compared to baseline.585

Electrical stimulation improved quality of life in the majority of RCTs that examined this outcome558,565,580,582 (Appendix Table F98). We could not conclude consistency in improvement across the studies because the studies used different tools to measure quality of life. Electrical stimulation did not reduce prevalence of detrusor overactivity or urgency UI in the few studies that reported this outcome578,583,586 (Appendix Table F99). One RCT found that discontinuation of the treatment did not differ between active and sham stimulation582 (Appendix Table F100). A cohort study found that 12 percent of women stopped using electrical stimulation at home at 2 years of followup.585

Clinical Effects of Magnetic Stimulation

A moderate level of evidence indicated that magnetic stimulation improved UI but did not increase urinary continence more than sham stimulation. Evidence of improved quality of life was low.

Five RCTs examined magnetic stimulation.587–591 The studies of magnetic stimulation included women with UI,588 stress UI,587,590 mixed,590 or predominant urgency UI589 (Appendix Table F81). Magnetic stimulation was described with different levels of detail using 10 Hz,588,591 15Hz,587,590 or 18.5Hz589 for 1,587 2,590 6,591 or 8 weeks.588,589 The studies compared active with sham stimulation using double blind,587,589,590 single blind,588 or open label591 designs.

Improvement in UI

Active magnetic stimulation, however, improved UI in two587,588 of three RCTs587–589 that examined this outcome (Appendix Table F101). A single RCT of pure stress UI demonstrated a greater increase in improvement rates.587 Pooled analysis demonstrated a 130 percent relative increase in improved UI587–589 (Appendix Table F102). Magnetic stimulation had to be administered in four women to achieve improvement in UI in one woman (Appendix Table F97).

Clinical Effects of Medical Devices

Evidence was insufficient to draw valid conclusions about the benefits of using intravaginal and intraurethral devices. Uncontrolled studies demonstrated improvement in UI, but also high discontinuation rates due to adverse effects.

Clinical outcomes with a variety of medical devices were reported in nonrandomized, noncontrolled studies568–572,574,575,593–608 (Appendix Table F26). Continence rates were 82 percent after using the CapSure (Re/Stor) continence 593 and 20 percent594 to 54 percent595 after using the Contiform intravaginal device. Rates of continence and improved UI were 58 percent598 to 69 percent596,597 after using the Conveen Continence Guard. Improvement in quality of life was reported by 50 percent600 to 59 percent601 of women after using the FemAssist silicone cup. The continence rate was 93 percent at 48 months after using the FemSoft urethral insert.602 Some studies reported discontinuation rates that varied from 27 percent601 to 41 percent.602 A few studies reported adverse effects in women after using the devices, including urinary tract infection in 31.3 percent, mild trauma in 6.7 percent, hematuria in 3.3 percent,602 local discomfort in 62 percent,597 acute bacterial cystitis in 5 percent, a small degree of fracture of the curvature of the device in 22 percent,594 or residual volume >100 ml in 5.4 percent.595

Clinical Effects of Bulking Agents for Refractory Stress UI

A low level of evidence suggests that bulking agents did not demonstrate improvement in UI when compared to placebo. Evidence was insufficient to draw valid conclusions about improvement in quality of life. Uncontrolled studies reported high rates of improvement, but also adverse effects.

Clinical outcomes after bulking agents compared to placebo or sham treatments were reported in two RCTs of 241 women609,610 (Appendix Table F81). The studies enrolled women with urodynamic stress UI and without detrusor overactivity. Women were treated with periurethral injections of autologous fat.610 Active treatments did not improve UI609,610 (Appendix Table F104). Periurethral injections of autologous fat did not improve the mean incontinence quality of life score610 (Appendix Table F105).

Uncontrolled studies reported outcomes after injection of copolymer system611 or nonendoscopic injection of nonanimal stabilized hyaluronic acid/dexranomer (NASHA/Dx) gel.612,613 Improvement rate after NASHA/Dx was 76 percent,613 improvement in quality of life was 67 percent,612 but 36 percent had adverse effects.613

Efficacy of Nonpharmacological Treatments for Urgency UI

Clinical Effects of Bladder Training

A low level of evidence indicated an improvement in UI with bladder training compared to usual care. Evidence of benefits from bladder training for urinary incontinence was insufficient.

Two RCTs examined bladder training compared to no active treatment.614,615

Continence

Urinary continence was reported in one RCT that found a borderline significant increase in continence rates with bladder training compared to usual care.614 (Appendix Table F106)

One study found clinically important improvement in quality of life measured with the Incontinence Impact Questionnaire639 (Appendix Table F107). The evidence from individual RCTs was insufficient to extrapolate results for all women with UI.

Clinical Effects of Percutaneous Tibial Nerve Stimulation

Percutaneous tibial nerve stimulation improved UI in adults with OAB.

Four RCTs examined clinical effects of percutaneous tibial nerve stimulation,617–620 including the Study of Urgent PC versus Sham Effectiveness in Treatment of Overactive Bladder Symptoms (SUmiT) trial617 and the Overactive Bladder Innovative Therapy Trial (OrBIT)618,621 (Appendix Table F108). The studies treated adults with either active stimulation with a current level of 0.5 to 9 mA at 20 Hz, or with sham stimulation.

Continence

No RCTs compared continence after percutaneous tibial nerve stimulation versus sham stimulation in adults with UI. Participants in OrBIT Trial reported 16 to 20 percent cure rates with 12 months of active stimulation.621 The study did not report cure rates with sham stimulation. Continence rates were 94 percent among women with predominant urgency UI and 91 percent in women with mixed UI in an uncontrolled trial.622 Continence did not differ with more frequent stimulation (three versus one time/week).623

Adverse Effects

Patients experienced ankle bruising (1 of 110, 0.9 percent), discomfort at the needle site (2 of 110, 1.8 percent), bleeding at the needle site (3 of 110, 2.7 percent), and tingling in the leg (1 of 110, 0.9 percent) without statistical significance when compared to sham stimulation.617 Treatment discontinuation did not differ with active versus sham stimulation. One patient did not complete the treatment because of aggravating pre-existing cardiac arrhythmia in an uncontrolled clinical trial of 39 subjects with voiding dysfunction.626

Efficacy of Nonpharmacological Treatments for Mixed UI

Clinical Effects of PFMT Combined With Bladder Training

A high level of evidence indicated significant benefits from PFMT combined with bladder training on urinary continence and improvement in UI. The evidence was low that this treatment reduced bother of UI and was insufficient that it improved quality of life.

Six publications of five RCTs examined PFMT combined with bladder training in adults with mixed UI.627–632

Continence

Urinary continence was significantly more common in women with PFMT combined with bladder training than with no active treatment (Appendix Table F109).627–629,631,632 One study reported very large significant increases in continence.632 Excluding that study, sensitivity analysis demonstrated smaller but still highly significant increases in continence with PFMT combined with bladder training.627,629 PFMT combined with bladder training needed to be administered to six women to achieve continence in one (Table 12).

Improvement in UI

PFMT combined with bladder training resulted in a significant improvement in UI in all studies that examined this outcome (Appendix Table F97).627–629,631 PFMT combined with bladder training had to be administered in three women to improve UI in one woman.

PFMT combined with bladder training reduced severity of UI (Appendix Table F110).627,632,633 One study found that self-reported severe UI was reduced by 82 percent.627 Another study demonstrated that self-reported bothersome UI was reduced by 31 percent.633 Use of absorbent pads for UI was reduced by 29 percent in one study.633 One study found a significant reduction in stress and urgency UI, but not in mixed UI632 (Appendix Table F100).

Quality of life was examined in one study that reported significant changes in IIQ score after treatment and at the 6 month-followup632 (Appendix Table F111). Evidence was insufficient to determine improvement in quality of life with PFMT combined with bladder training (Table 13).

Improvement in severity of incontinence and quality of life with nonpharmacological treatments compared to no active treat.

Clinical Effects of Continence Services That Were Implemented by Specialized Health Care Providers

A low level of evidence indicated no consistent benefits from continence services implemented by specialized health care providers on continence and improvement of UI when compared to usual care. Promising results on improved quality of care need further confirmation. Comparison across the studies was difficult because of the variety of interventions that constituted complex continence services.

Clinical outcomes were reported in four RCTs that compared continence services with usual care634–637 (Appendix Table F81). Continence services were described with different levels of detail and usually included advice on diet and fluids, bladder training, pelvic floor muscle education and awareness, lifestyle advice,634 use of an audiovisual program, calendar, counseling, voiding schedule recommendations, and assessing self-care methods.635 The services were implemented by continence nurse advisors636,637 and consulting urogynecologists.636 The studies included subjects with any UI.

Continence

Continence was reported in three studies (Appendix Table F112).634–636 The Continence Efficacy Intervention Program increased the rate of continence when compared to conventional care by 556 percent in women with pure stress UI.635 Among every 1,000 women treated with the program, 743 cases of continence would be attributable to the Continence Efficacy Intervention Program.635 The largest RCT of 2,248 women with mixed UI reported smaller benefits from continence service than with usual care, with 90 additional cases of continence attributable to active treatment per 1,000 treated.634 Pooled analysis of three studies found a significant relative increase of 58 percent with continence services, but no significant differences in absolute rates of continence.634–636

Improvement in Incontinence

Improvement was inconsistent across the studies (Appendix Table F113).634,637 Pooled analysis of two studies634,637 found significant improvement in UI (33 percent) but no significant differences in absolute rates of improved incontinence. Continence services improved quality of life (Appendix Table F114).634,638 With services delivered by a continence nurse and a multidisciplinary team consisting of a general practitioner, urologist, and physiotherapist, women did not experience pain or discomfort at 1 year of followup (RR 3.88, 95 percent CI, 1.57 to 9.58), did not have a UI related problem with usual activities (RR 3.74, 95 percent CI, 1.66 to 8.44), and did not complain about anxiety/depression more often than with usual care.638 Two to four women needed to be treated with a multidisciplinary team to achieve improved quality of life in one woman.638 Another study that compared continence services to usual care found that continence services resulted in a 21 percent relative increase in the proportion of women satisfied with their level of current urinary symptoms for the rest of their lives (RR 1.21, 95 percent CI, 1.12 to 1.30).634 Such services needed to be provided to nine women to achieve improved quality of life in one woman.634 Several RCTs reported quality of life scores with continence services when compared to usual care (Appendix Table F115).635,636,638–640 The differences rarely achieved statistical significance. Significant differences were not consistent across domains of quality of life (Table 13). The magnitude of the differences was unlikely of any clinical importance.

Clinical Effects of Group Behavioral Modification Program (BMP)

Group BMP was a combination of PFMT and bladder-training education.641 Evidence from one RCT was insufficient for valid conclusions about the effectiveness of behavioral modification programs in women with mixed UI.

A single study randomized 44 adult women with mixed UI to a behavioral modification program consisting of a group lecture by two trained urology nurses with individualized meetings and assessment of knowledge and modification of behavior.641 The control group received no treatments for UI. The behavioral modification program significantly improved UI (ARD 0.38, 95 percent CI, 0.13 to 0.63).641 The program improved UI in every third woman (NNT 3 95 percent CI, 2 to 8) when compared to no active treatment.641 Improvement in UI was achieved in 379 per 1,000 treated women (95 percent CI, 126 to 632).

Clinical Effects of Weight Loss

A moderate level of evidence indicated improvement in UI after weight loss and exercise in obese women. The evidence was insufficient to conclude if there was an increase in continence or improved quality of life.

Three studies reported clinical outcomes after weight loss programs (Appendix Table F116).642–644 One RCT compared an intensive 6-month weight loss program to no active treatment.642 The trial enrolled women with a BMI of 25 to 50kg/m2 with any daily UI. The program included self-administered diet, exercise, and behavior modification, and aimed to produce an average loss of 7 to 9 percent of initial body weight. The second study treated women with a BMI between 25 and 45 kg/m2 and at least four incontinent episodes per week.643 A diet study provided a 3-month standard low calorie liquid diet (800 kcals/day or less), increased physical activity to 60 minutes/day, and training by a nutritionist, exercise physical therapist, or behavioral therapist.643

Continence

Improvement in UI

Significant improvement in UI was demonstrated in both studies (Appendix Table F116).642,643 Weight loss had to be maintained in four women to achieve improvement in UI in one woman (Appendix Table F97). Bayesian analysis also found improvement in UI after weight loss in obese women with UI.

Quality of life after weight loss was examined in two RCTs (Appendix Table F117).642,644 Women reported that UI became somewhat or much less of a problem more often after 6 months of treatment. The PRIDE study (Program to Reduce Incontinence by Diet and Exercise) examined the effects of intensive weight loss on sexual function in overweight and obese women with BMI of 25 to 50 kg/m2 and daily UI.644 The study found no significant increase in the odds of overall sexual satisfaction (OR 1.28, 95 percent CI, 0.83 to 1.99) or sexual desire (OR 1.12, 95 percent CI, 0.79 to 1.61).644

An uncontrolled study of a low calorie diet and exercise with a target loss of 5 to 10 percent of body weight reported significant improvement in quality of life when compared to baseline.645

Clinical Outcomes of Soy-Enriched Diet

One study tested the effects of the soy-enriched diet on urogenital symptoms in perimenopausal and postmenopausal Thai women, and demonstrated no reduction in UI (Appendix Table F119).646

Clinical Effects of Acupuncture

Evidence was insufficient to conclude improvement in UI after acupuncture. Low evidence suggested possible improvement in quality of life after active acupuncture.

Clinical outcomes of active acupuncture versus acupuncture of inactive points were reported in two RCTs of 137 women647,648 (Appendix Table F81) and one uncontrolled study.649 The RCTs enrolled women with symptoms of overactive bladder with urgency incontinence647 or with stress UI.648 Active acupuncture did not resolve urgency UI647 (Appendix Table F120). An uncontrolled study reported an improvement rate of 80 percent in older women for whom previous treatments had failed.649 Improvement in quality of life was inconsistent across two RCTs647,648 (Appendix Table F121).

Comparative Effectiveness of Nonpharmacological Treatments

We concluded with high confidence that PFMT alone and in combination with bladder training or biofeedback, electrical stimulation, or weight loss with exercise was effective to achieve continence and improvement in UI. These treatments had comparable effects when compared to each other. Evidence was not sufficient to conclude better effects from medical devices or bulking agents when compared to each other.

Clinical outcomes with one nonpharmacological treatment versus another were reported in 54 RCTs (Appendix Table F81). These trials rarely compared the same treatment effects, which decreased the level of evidence to low or insufficient.

A high level of evidence indicated no difference in UI outcomes between supervised PFMT combined with bladder training and self-administered PFMT.

Supervised PFMT combined with bladder training was not more effective than self-administered PFMT650–654 (Appendix Table F122). Continence rates were similar between the two interventions (Table 15).650–654 Improvement in UI was similar between supervised and self-administered PFMT (Appendix Table F123).650–654 Rates of treatment failure and treatment discontinuation did not differ between the two treatments (Appendix Table F122).650–653 One RCT reported better patient satisfaction with supervised versus self-administered PFMT in 44 women with urodynamic stress UI.652

Differences in quality of life were inconsistent across studies. One RCT did not demonstrate better quality of life with supervised versus self-administered PFMT in 88 women with mixed UI655 (Appendix Table F125). Supervised PFMT versus self-administered PFMT worsened two domains of King’s Health Questionnaire (physical limitations and physical activity limitations), with no differences in other domains in 61 women with urodynamic stress UI651 (Appendix Table F126).

Prevalence of UI did not differ between supervised and self-administered PFMT.650,655–657 Only one RCT of intensive PFMT under the supervision of a physical therapist for 6 months in 52 women with urodynamic stress UI demonstrated no sustained reduction in prevalence of severe UI (RR 0.18, 95 percent CI, 0.02 to 1.33) and urgency UI (RR 0.37, 95 percent CI, 0.12 to 1.18) at 15 years (Appendix Table F125).650

The studies of individual PFMT did not report better outcomes than group PFMT in individual RCTs of women with different types of UI (Appendix Table F127).658,659

Comparative Effectiveness of PFMT With and Without Biofeedback Using Vaginal EMG Probe

A high level of evidence indicated no differences in clinical outcomes between PFMT with or without biofeedback using vaginal EMG probe.

The studies that compared PFMT with or without biofeedback using vaginal EMG probe found no consistent differences in continence (Table 15, Appendix Table F124). Nor did quality of life rates differ.660,661 Scores of Leakage Index,660,662 Social Activity Index,660 Incontinence Impact Questionnaire,663 or IIQ-7 scores664 did not differ between PFMT with and without biofeedback (Appendix Table F128). Prevalence and impact of UI did not differ between treatments, either660,663 (Appendix Table F129).

Comparative Effectiveness of PFMT and Electrical Stimulation

A moderate level of evidence suggested no differences in UI with PFMT and electrical stimulation. PFMT did not result in better outcomes than electrical stimulation563,665,666 (Appendix Table F130). Rates of improvement in UI and treatment failure also did not differ between the two treatments563,665,666 (Appendix Table F123).

Evidence was insufficient to draw conclusions about comparative effectiveness of PFMT combined with electrical stimulation versus PFMT alone. A combination of PFMT with electrical stimulation reduced the frequency of UI and improved quality of life more often than PFMT alone667 (Appendix Table F131).

Comparative Effectiveness of PFMT and Medical Devices

A moderate level of evidence indicated no difference in outcomes for UI treated with PFMT compared to vaginal cones. Evidence was insufficient to draw valid conclusions about comparative effectiveness of PFMT and vaginal rings and balls.

Relative benefits of PFMT compared to medical devices were inconsistent across the studies. The rates of continence or improvement in predominant stress UI did not differ between PFTM and vaginal cones561,563,668 (Appendix Table F132). PFMT combined with biofeedback did not result in greater continence rates than use of vaginal cones669 (Appendix Table F131). Rates of treatment discontinuation did not differ between the two treatments.669 PFMT with biofeedback resulted in the same quality of life as vaginal cones670,671 (Appendix Table F133).

PFMT using weighted vaginal balls 50 to 100 g resulted in increased continence rates and improvement in UI compared to regular PFMT in one study that examined this association672 in 37 women with stress UI (Appendix Table F131).

Comparative Effectiveness of Circular Muscle Exercises and PFMT

Continence and improvement in predominant stress UI were greater with circular muscle exercises (Paula method) than PFMT674 in women with UI (Appendix Table F134). Quality of life was reported in two RCTs that compared circular muscle exercises with PFMT, with no consistent differences674,675 (Appendix Table F135). With circular muscle exercises, women experienced less “leakage annoyance” but not less frequency of UI674 (Appendix Table F136). Back pain was more common with the Paula method than with regular PFMT.674

Comparative Effectiveness of Interventions To Increase Adherence to PFMT

Evidence was insufficient to draw valid conclusions about comparative effectiveness of interventions to increase adherence to PFMT.

Adding personal reminders to enhance adherence to PFMT did not improve outcomes in 129 women with UI677 (Appendix Table F139). Providing women with an audiocassette tape to enhance adherence to PFMT increased routine pelvic floor muscle exercise more often than usual verbal instructions for PFMT.678 Women performed pelvic floor exercises twice per day more often after listening to audiocassette tapes.678 Providing audiocassette tapes resulted in better adherence to PFMT in 698 women per 1,000 treated (Appendix Table F139).

Comparative Effectiveness of PFMT in Different Positions

Available evidence did not indicate differences in benefits between different regimens and combinations of PFMT treatments.

PFMT with EMG biofeedback in both supine and upright positions versus supine position resulted in the same outcomes in 44 women with stress UI.679

Comparative Effectiveness of Electrical Stimulation Methods

Evidence was insufficient to conclude comparative effectiveness of electrical stimulation and other nonpharmacological treatments for UI.

Comparative effectiveness of once versus three times per week posterior tibial nerve simulation resulted in the same outcomes in 35 subjects with urgency UI who failed oxybutynin treatment.623

Frequency of UI episodes, pad test, quality of life, and treatment discontinuation rates did not differ between intravaginal electrical stimulation with or without biofeedback680 (Appendix Table F131).

Electrical stimulation compared to the use of vaginal cones resulted in the same rates of continence, improvement in UI, and discontinuation of treatments due to failure to improve UI563 (Appendix Table F131).

Physical therapy that included PFMT in combination with biofeedback compared to physical therapy alone increased rates of continence and improvement in UI in one study of 40 women with stress UI.661

Comparative Effectiveness of Various Bulking Agents for Refractory Stress UI

Seven RCTs examined clinical outcomes after different bulking agents in women with pure stress UI and did not find consistent differences686–692 (Appendix Table F144). Continence was greater after Macroplastique versus Contigen® in 260 women693 and after autologous myoblasts and fibroblasts versus collagen in 63 women.690 Autologous myoblasts and fibroblasts versus collagen improved quality of life scores in 63 women with intrinsic sphincter insufficiency or stress UI690 (Appendix Table F145). Adverse effects were more common with Zuidex Implacer than with Contigen Endoscopic guidance in 344 women with stress UI692 (Appendix Table F146). Continence rates were greater with durasphere than with contigen in one RCT in 52 women with stress UI.683

Comparative Effectiveness of Bladder Training

Evidence indicated that continence did not differ between bladder training combined with PFMT and bladder training alone. Evidence was insufficient to draw conclusions based on other tested comparisons.

Bladder training by listening to an audiotape daily improved UI more often than bladder training without the audiotape694 (Appendix Tables F131 and F147).

Continence did not differ between bladder training and PFMT.660 Satisfaction with current UI and feelings of no impact from UI on quality of life did not differ between bladder training and PFMT.561 Transcutaneous tibial nerve combined with bladder and PFMT increased rates of continence or clinically important reduction in daily UI episodes in older women with urgency UI compared to bladder and PFMT (Appendix Table F148). Bladder training combined with PFMT did not increase continence or improve UI more often than bladder training alone93,695 (Appendix Table F149). Bladder training did not increase continence more often than use of vaginal cones (Appendix Table F131).561

Outpatient continence services involving bladder retraining and physical therapy resulted in the same continence as treatment with an inpatient 5-day hospital stay in 74 women with any UI696 (Appendix Table F131).

The Continence Efficacy Intervention Program increased continence rates more often than PFMT in 48 women with stress or mixed UI.635 Quality of life scores, however, did not differ between the two treatments635 (Appendix Table F150). Face-to-face behavioral consultation by the nurse specialist giving digital assessment feedback on pelvic floor contraction resulted in the same continence as video conferences with continence nurses in 32 older women with symptoms of urgency or stress incontinence697 (Appendix Table F131).

Evidence was insufficient to draw conclusions about comparative effectiveness of group versus individual therapy for UI.

Women reported lower benefits from group versus individual physical therapy sessions for mixed UI at 5 months of followup (RR 0.79, 95 percent CI, 0.65 to 0.98) in one RCT.698 Symptom severity or quality of life outcomes did not differ between treatment groups.698

Comparative Effectiveness of Behavioral Weight Loss and Education

Evidence was insufficient to conclude comparative effectiveness between behavioral weight loss intervention and education. Women reported more frequent improvement in mixed UI (defined as more than 70 percent reduction in weekly UI episodes) at 12 months with a behavioral weight loss intervention than with education699 (Appendix Table F131). The differences remained significant only for urgency UI at 18 months posttreatment.699

Indirect comparisons indicated similar effectiveness of nonpharmacological treatments on continence.

We evaluated the effectiveness of different nonpharmacological treatment compared to no active treatment. Such indirect evidence from all RCTs indicated that all active treatments increased continence rates without evident differences (Figure 21). Absolute rate differences were significant for electrical stimulation, PFMT, and PFMT combined with bladder training. Attributable cases of continence were 299 per 1,000 for PFMT compared to 162 cases for electrical stimulation, and 166 cases for PFMT combined with bladder training. Rates of continence were similar between different treatments: 38 percent of women became continent with PFMT, 23 percent became continent with electrical stimulation, and 21 percent became continent with PFMT combined with bladder training.

Continence with nonpharmacological treatments for UI when compared to no active treatment (pooled with random effects estimates from head-to-head RCTs).

Statistical indirect comparisons were difficult because of substantial variability in continence rates with control treatment (Figure 21). We analyzed which factors potentially contribute to such differences in continence with the control treatment, and found no statistically significant associations.

Comparative Effectiveness of Nonpharmacological Treatments When Compared to Drugs or Combined Modalities

Evidence was insufficient to draw valid conclusions about comparative effectiveness and safety of nonpharmacological treatments compared to drugs or combined modalities (Table 16).

Comparative Effectiveness of Nonpharmacological Treatments When Compared to Drugs or Combined Modalities for Stress UI

Duloxetine

Evidence was insufficient to conclude comparative effectiveness or harms of duloxetine combined with PFMT compared to duloxetine alone.

One study, Duloxetine/Pelvic Floor Muscle Training Clinical Trial Group, compared clinical outcomes of duloxetine with and without PFMT in 201 women with stress UI.393 Women were enrolled in 17 continence clinics in the Netherlands, the United Kingdom, and the United States, and randomized to one of four combinations of 80 mg duloxetine daily, placebo, PFMT, and imitation PFMT.393 Combined treatment with duloxetine and PFMT resulted in a greater reduction in UI episode frequency than PFMT alone.393 Response rates (defined as >50 percent decrease in incontinent episode frequency), clinically important improvement in I-QOL score, and perceived treatment success did not differ between treatment groups.393 Women who completed paper diaries at each visit experienced greater improvement in UI, quality of life, and perceived treatment success with PFMT than with duloxetine. Adverse effects and treatment discontinuation due to adverse effects were more often associated with duloxetine combined with PFMT than with PFMT or placebo.393

Comparative Effectiveness of Nonpharmacological Treatments When Compared to Drugs or Combined Modalities for Urgency UI

Oxybutynin

Oxybutynin Compared to Biofeedback-Assisted PFMT

Adjustable doses of oxybutynin and behavioral biofeedback-assisted PFMT resulted in the same rates of continence and improvement in UI in 197 older women with urgency or predominant urgency UI.418,437,438 Women perceived their bladder condition as “much better”437 and were completely satisfied with the treatment more often with biofeedback-assisted training.438 Adverse effects, including inability to void, constipation, and dry mouth, were less common with biofeedback-assisted PFMT than with oxybutynin.437

Oxybutynin Compared to Electrical Stimulation

Available limited evidence was insufficient to draw valid conclusions about comparative effectiveness of electrical stimulation compared to oxybutynin or with combined treatments compared to electrical stimulation alone.

Electrical stimulation with a 10-Hz frequency resulted in greater effects on UI episodes and quality of life scores than oxybutynin 7.5 mg/day.443 The rates of resolved urgency and reduction in OAB symptoms did not differ between the electrical stimulation and drug therapy groups443 (Appendix Table F151).

Tolterodine

Evidence was insufficient to conclude comparative effectiveness and safety of tolterodine combined with PFMT, bladder control techniques, fluid management versus tolterodine alone. The Urinary Incontinence Treatment Network compared clinical outcomes in 307 women with predominant urgency UI treated with a combination of tolterodine plus supervised behavioral training versus tolterodine alone701–703 (Appendix Table F152). Combined therapy resulted in greater rates of complete satisfaction with therapy at the end of the treatment and at 8 months followup.702 The rates of perceived improvement with UI as “better” or “much better” were also higher with combined treatment at the end of the trial and at 8 months followup.702

Standard educational programs that included printed information and an explanation about OAB, medication use, and behavioral treatments combined with tolterodine were compared to tolterodine alone in one RCT of 84 adults with OAB (Kegel exercise, bladder stretching, fluid regulation with medication treatment alone).704 Self-reported perception of treatment success and the use of behavior modification therapies were greater with combined therapy than with tolterodine alone.704 More women used Kegel exercises and urge suppression techniques, regulated fluid intake, and limited caffeine intake with combined treatment than with drugs alone. Patient satisfaction was associated with changes in Urogenital Distress Inventory (UDI) score, but not with a reduction in UI daily episodes.705 After multivariable analysis, every 10-point increase in UDI score was associated with 11 percent higher odds of treatment satisfaction (OR 1.11, 95 percent CI, 1.04 to 1.19).705

Tolterodine Versus Percutaneous Tibial Nerve Stimulation

Evidence from one study was insufficient to conclude better effectiveness of percutaneous tibial nerve stimulation compared to tolterodine. The Overactive Bladder Innovative Therapy trial compared clinical outcomes with percutaneous tibial nerve stimulation and extended-release tolterodine in 100 adults with urinary frequency706 (Appendix Table F153). Patient assessment and investigator assessment of improvement or cure were greater with stimulation than with tolterodine. Self-reported change in health-related quality of life score did not differ between stimulation and drug treatment.706 Subjects reported worsening of the symptoms less often with stimulation than with the drug.706

Tolterodine Versus Intravaginal Electrical Stimulation

Evidence from one RCT was insufficient to conclude better effectiveness of intravaginal electrical stimulation compared to tolterodine.707 Women with overactive bladder and predominant urgency UI experienced improvement in symptoms from baseline with electrical stimulation and with tolterodine, without significant differences between treatment groups.707 Dry mouth was less common with stimulation than with the drug (ARD −0.26, 95 percent CI, −0.41 to −0.11).707 Both treatments improved quality of life. Improvement in severity of urinary symptoms and in social and personal relationships were significantly greater with electrical stimulation than with tolterodine at 6 months followup.707

The Tolterodine Scandinavian Study Group compared clinical outcomes with tolterodine combined with simplified bladder training versus tolterodine alone. This randomized trial enrolled adults with OAB, including 75 percent of women.708 The number of UI episodes and perceived improvement in symptoms did not differ between treatment groups.708 Symptom deterioration tended to be lower with combined treatment, but the difference did not reach statistical significance.708 The total number of adverse effects, including dry mouth, headache, and constipation, were similar between combined treatment and drug treatment alone.708

Solifenacin

Evidence was insufficient to conclude comparative effectiveness and safety of a combination of solifenacin with bladder training and the drug alone. The SOLifenacin Alone and with simplified bladder Re-training (SOLAR) RCT compared clinical outcomes of flexible-dose solifenacin 5/10 mg with and without bladder training in patients with overactive bladder709 (Appendix Table F154). Combined therapy was better in reducing micturition frequency.709 Quality of life scores did not differ between treatment groups.709 Adverse effects did not differ between treatments.709

Trospium

Evidence was insufficient to conclude comparative effectiveness and safety of trospium and electrical stimulation. Trospium was compared with intravaginal electrical stimulation in women with overactive bladder syndrome326 (Appendix Table F155). Improvement in UI did not differ between trospium and electrical stimulation.326 Both treatments improved VAS urgency severity and Beck Depression Inventory scores when compared to baseline levels. However, neither post-treatment VAS urgency severity nor Beck Depression Inventory scores differed between the drug and electrical stimulation. Dry mouth was more common with drug (ARD 0.29, 95 percent CI, 0.07 to 0.52).326

Darifenacin

Darifenacin Compared to Behavioral Modification Program

We found insufficient evidence to conclude differences in benefits and harms of darifenacin combined with behavioral modification compared to darifenacin alone. The ABLE trial randomized adults with OAB to the flexible dose of darifenacin (7.5 to 15 mg/day) alone or combined with behavioral brochures on modification of diet and daily habits and training for pelvic floor muscle exercise.710 The differences between the two groups for both the Overactive Bladder Questionnaire (OAB-q) and the Overactive Bladder Satisfaction with Treatment Questionnaire (OAB-SAT-q) at week 12 were not significant. However, the rate of adverse effects leading to discontinuation of treatment was higher in the combined treatment group (RR 3.24, 95 percent CI, 1.34 to 7.86).710